9-136506764-C-T

Variant names:

• chr9-136506764-C-T
• rs756972680
• NM_017617.5:c.3853G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP3 BP6 BS1 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10 B:2
• Conservation: PhyloP100: 3.81
• Publications: 7 publications found

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

ACMG classification

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 submissions are: {Benign=1, Uncertain_significance=6, Likely_benign=1}.
• 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	c.3853G>A	p.Val1285Met	missense_variant	Exon 23 of 34	ENST00000651671.1	NP_060087.3
NOTCH1	XM_011518717.3	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	c.3853G>A	p.Val1285Met	missense_variant	Exon 23 of 34		NM_017617.5	ENSP00000498587.1

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152238 Hom.: 0 Cov.: 34

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: 13 AN: 236138 AF XY: 0.0000776

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.: 1 Cov.: 34 AF XY: 0.0000871 AC XY: 63 AN XY: 723608

African (AFR) AF: 0.0000600 AC: 2 AN: 33346

American (AMR) AF: 0.00 AC: 0 AN: 44056

Ashkenazi Jewish (ASJ) AF: 0.0000385 AC: 1 AN: 26000

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39366

South Asian (SAS) AF: 0.0000352 AC: 3 AN: 85342

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51718

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5766

European-Non Finnish (NFE) AF: 0.0000766 AC: 85 AN: 1109684

Other (OTH) AF: 0.000266 AC: 16 AN: 60118

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152238 Hom.: 0 Cov.: 34 AF XY: 0.0000672 AC XY: 5 AN XY: 74374

African (AFR) AF: 0.00 AC: 0 AN: 41448

American (AMR) AF: 0.000196 AC: 3 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68046

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000869

ExAC AF: 0.0000581 AC: 7

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10 Benign:2

Revision: criteria provided, conflicting classifications

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:1 Benign: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	T
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.73	D
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Uncertain	0.56	D
MutationAssessor	Uncertain	2.0	M
PhyloP100		3.8
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.63
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.98	D
Vest4		0.63
MutPred		0.53		Gain of phosphorylation at T1281 (P = 0.2143);
MVP		0.82
MPC		1.1
ClinPred		0.26	T
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

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

Other links and lift over

dbSNP: rs756972680; hg19: chr9-139401216; COSMIC: COSV104586603;