chr9-136506764-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP3BP6BS1BS2

The NM_017617.5(NOTCH1):c.3853G>A(p.Val1285Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000834 in 1,607,634 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1285L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000082 ( 1 hom. )

Consequence

NOTCH1
NM_017617.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10B:2

Conservation

PhyloP100: 3.81

Publications

7 publications found

Variant links:

COSMIC-nc: COSV104586603

Genes affected

NOTCH1 (HGNC:7881): (notch receptor 1) This gene encodes a member of the NOTCH family of proteins. Members of this Type I transmembrane protein family share structural characteristics including an extracellular domain consisting of multiple epidermal growth factor-like (EGF) repeats, and an intracellular domain consisting of multiple different domain types. Notch signaling is an evolutionarily conserved intercellular signaling pathway that regulates interactions between physically adjacent cells through binding of Notch family receptors to their cognate ligands. The encoded preproprotein is proteolytically processed in the trans-Golgi network to generate two polypeptide chains that heterodimerize to form the mature cell-surface receptor. This receptor plays a role in the development of numerous cell and tissue types. Mutations in this gene are associated with aortic valve disease, Adams-Oliver syndrome, T-cell acute lymphoblastic leukemia, chronic lymphocytic leukemia, and head and neck squamous cell carcinoma. [provided by RefSeq, Jan 2016]

NOTCH1 Gene-Disease associations (from GenCC):

Adams-Oliver syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Illumina, Orphanet
Adams-Oliver syndrome 5
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
aortic valve disease 1
Inheritance: AD Classification: STRONG Submitted by: G2P, PanelApp Australia
connective tissue disorder
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
leukodystrophy
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
familial bicuspid aortic valve
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
familial thoracic aortic aneurysm and aortic dissection
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

NOTCH1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.748

BP6

Variant 9-136506764-C-T is Benign according to our data. Variant chr9-136506764-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 450338.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0000825 (120/1455396) while in subpopulation MID AF = 0.00208 (12/5766). AF 95% confidence interval is 0.0012. There are 1 homozygotes in GnomAdExome4. There are 63 alleles in the male GnomAdExome4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High AC in GnomAd4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOTCH1	NM_017617.5 link	c.3853G>A	p.Val1285Met	missense_variant	Exon 23 of 34	ENST00000651671.1	NP_060087.3	P46531
NOTCH1	XM_011518717.3 link	c.3130G>A	p.Val1044Met	missense_variant	Exon 20 of 31		XP_011517019.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOTCH1	ENST00000651671.1 link	c.3853G>A	p.Val1285Met	missense_variant	Exon 23 of 34		NM_017617.5	ENSP00000498587.1		P46531

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000551

AC:

AN:

236138

AF XY:

0.0000776

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000298

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000752

Gnomad OTH exome

AF:

0.000522

GnomAD4 exome

AF:

0.0000825

AC:

120

AN:

1455396

Hom.:

Cov.:

AF XY:

0.0000871

AC XY:

AN XY:

723608

show subpopulations

African (AFR)

AF:

0.0000600

AC:

AN:

33346

American (AMR)

AF:

0.00

AC:

AN:

44056

Ashkenazi Jewish (ASJ)

AF:

0.0000385

AC:

AN:

26000

East Asian (EAS)

AF:

0.0000254

AC:

AN:

39366

South Asian (SAS)

AF:

0.0000352

AC:

AN:

85342

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51718

Middle Eastern (MID)

AF:

0.00208

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000766

AC:

AN:

1109684

Other (OTH)

AF:

0.000266

AC:

AN:

60118

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000920

AC:

AN:

152238

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74374

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41448

American (AMR)

AF:

0.000196

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000162

AC:

AN:

68046

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000869

ExAC

AF:

0.0000581

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:5

Nov 16, 2020

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Reported in one proband with hypoplastic left heart syndrome, though clinical and segregation details are not available (Helle et al., 2019); Reported in ClinVar as a variant of uncertain significance but additional evidence is not available (ClinVar Variant ID# 450338; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25587027, 30511478) -

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The NOTCH1 p.Val1285Met variant was identified in 1/49 probands with hypoplastic left heart syndrome (Helle_2017_PMID:30511478) and 1/108 B-chronic lymphocytic leukemia patients (Athanasakis_2014_PMID:25587027). The variant was identified in dbSNP (ID: rs756972680), ClinVar (classified as uncertain significance by GeneDx and Invitae for Adams-Oliver Syndrome 5) and LOVD 3.0 (classified as uncertain significance by VKGL-NL). The variant was identified in control databases in 14 of 267496 chromosomes at a frequency of 0.00005234 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Other in 3 of 6838 chromosomes (freq: 0.000439), European (non-Finnish) in 9 of 121848 chromosomes (freq: 0.000074), South Asian in 1 of 29434 chromosomes (freq: 0.000034) and Latino in 1 of 34386 chromosomes (freq: 0.000029), but was not observed in the African, Ashkenazi Jewish, East Asian, or European (Finnish) populations. The p.Val1285 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Adams-Oliver syndrome 5

Uncertain:1Benign:1

Dec 20, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 15, 2022

Genome-Nilou Lab

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial thoracic aortic aneurysm and aortic dissection

Uncertain:1

Sep 27, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.V1285M variant (also known as c.3853G>A), located in coding exon 23 of the NOTCH1 gene, results from a G to A substitution at nucleotide position 3853. The valine at codon 1285 is replaced by methionine, an amino acid with highly similar properties. This variant was detected in one individual with hypoplastic left heart syndrome (Helle E et al. Genet. Epidemiol., 2019 03;43:215-226). This alteration has also been reported in an ischemic stroke cohort (Alkhamis FA et al. Funct Integr Genomics, 2023 Mar;23:102). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Hypoplastic left heart syndrome

Uncertain:1

University of Washington Center for Mendelian Genomics, University of Washington

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:research

- -

Aortic valve disease 1;C4014970:Adams-Oliver syndrome 5

Uncertain:1

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NOTCH1 NM_017617.5 exon 23 p.Val1285Met (c.3853G>A): This variant has not been reported in the literature but is present in 0.007% (9/121848) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/9-139401216-C-T). This variant is present in ClinVar (Variation ID:450338). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Aortic valve disease 1

Uncertain:1

Mar 15, 2022

Genome-Nilou Lab

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Aug 14, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: NOTCH1 c.3853G>A (p.Val1285Met) results in a conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.5e-05 in 236138 control chromosomes (gnomAD). The observed variant frequency is approximately 88 fold of the estimated maximal expected allele frequency for a pathogenic variant in NOTCH1 causing Adams-Oliver Syndrome 5 (6.3e-07), strongly suggesting that the variant is benign. c.3853G>A has been reported in the literature in one individual affected with Hypolastic Left Heart Syndrome without evidence of segregation (Helle_2019). This report does not provide unequivocal conclusions about association of the variant with Adams-Oliver Syndrome 5. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 30511478). Five ClinVar submitters have assessed this variant since 2014: four classified the variant as uncertain significance and one as benign. Based on the evidence outlined above, the variant was classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.040

BayesDel_noAF

Benign

-0.090

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.73

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.95

M_CAP

Pathogenic

0.31

MetaRNN

Pathogenic

0.75

MetaSVM

Uncertain

0.56

MutationAssessor

Uncertain

2.0

PhyloP100

3.8

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-2.3

REVEL

Uncertain

0.63

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.0080

Polyphen

0.98

Vest4

0.63

MutPred

0.53

Gain of phosphorylation at T1281 (P = 0.2143);

MVP

0.82

MPC

1.1

ClinPred

0.26

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.21

Mutation Taster

=72/28

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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chr9-136506764-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over