9-136506764-C-T

Position:

chr9-136506764-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PP2PP3BP6BS2

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).

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

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), NOTCH1. . Trascript score misZ 3.6761 (greater than threshold 3.09). GenCC has associacion of gene with familial bicuspid aortic valve, familial thoracic aortic aneurysm and aortic dissection, Adams-Oliver syndrome, connective tissue disorder, Adams-Oliver syndrome 5, aortic valve disease 1.

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 submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=6}.

BS2

High AC in GnomAd4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOTCH1	NM_017617.5 linkuse as main transcript	c.3853G>A	p.Val1285Met	missense_variant	23/34	ENST00000651671.1	NP_060087.3
NOTCH1	XM_011518717.3 linkuse as main transcript	c.3130G>A	p.Val1044Met	missense_variant	20/31		XP_011517019.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOTCH1	ENST00000651671.1 linkuse as main transcript	c.3853G>A	p.Val1285Met	missense_variant	23/34		NM_017617.5	ENSP00000498587	P1

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

GnomAD3 exomes

AF:

0.0000551

AC:

AN:

236138

Hom.:

AF XY:

0.0000776

AC XY:

AN XY:

128840

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 SAS exome

AF:

0.0000340

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

Gnomad4 AFR exome

AF:

0.0000600

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000385

Gnomad4 EAS exome

AF:

0.0000254

Gnomad4 SAS exome

AF:

0.0000352

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000766

Gnomad4 OTH exome

AF:

0.000266

GnomAD4 genome

AF:

0.0000920

AC:

AN:

152238

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.00

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

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 16, 2020	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) -
Uncertain significance, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	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. -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Adams-Oliver syndrome 5

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 19, 2023	- -

Familial thoracic aortic aneurysm and aortic dissection

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 27, 2023

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

Uncertain significance, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

- -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Mar 30, 2021

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

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Mar 15, 2022

- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Aug 14, 2023

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

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

MutationTaster

Benign

1.0

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over