rs200207651

chr9-136508926-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2 BP4_Strong BP6_Very_Strong BS2

The NM_017617.5(NOTCH1):c.3115G>A(p.Gly1039Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000476 in 1,549,454 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00060 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00046 (0 hom.)
• Consequence: NOTCH1 NM_017617.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 4.20

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]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• PP2: Missense variant where missense usually causes diseases, NOTCH1
• BP4: Computational evidence support a benign effect (MetaRNN=0.010801673).
• BP6: Variant 9-136508926-C-T is Benign according to our data. Variant chr9-136508926-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 264180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-136508926-C-T is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 91 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOTCH1	NM_017617.5	c.3115G>A	p.Gly1039Ser	missense_variant	19/34	ENST00000651671.1
NOTCH1	XM_011518717.3	c.2392G>A	p.Gly798Ser	missense_variant	16/31

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOTCH1	ENST00000651671.1	c.3115G>A	p.Gly1039Ser	missense_variant	19/34		NM_017617.5	P1

Frequencies

GnomAD3 genomes AF: 0.000598 AC: 91 AN: 152246 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000723

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00489

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000456

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000829 AC: 128 AN: 154310 Hom.: 0 AF XY: 0.000693 AC XY: 57 AN XY: 82258

Gnomad AFR exome AF: 0.000126

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.000471

Gnomad EAS exome AF: 0.000182

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00522

Gnomad NFE exome AF: 0.000603

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000462 AC: 646 AN: 1397090 Hom.: 0 Cov.: 35 AF XY: 0.000451 AC XY: 311 AN XY: 689172

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.000516

Gnomad4 EAS exome AF: 0.0000558

Gnomad4 SAS exome AF: 0.0000126

Gnomad4 FIN exome AF: 0.00491

Gnomad4 NFE exome AF: 0.000336

Gnomad4 OTH exome AF: 0.000397

GnomAD4 genome AF: 0.000597 AC: 91 AN: 152364 Hom.: 0 Cov.: 34 AF XY: 0.000765 AC XY: 57 AN XY: 74512

Gnomad4 AFR AF: 0.0000721

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00489

Gnomad4 NFE AF: 0.000456

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000302 Hom.: 0

Bravo AF: 0.000234

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000244 AC: 1

ESP6500EA AF: 0.000365 AC: 3

ExAC AF: 0.000251 AC: 26

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Adams-Oliver syndrome 5 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 13, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Aug 14, 2023

Variant summary: NOTCH1 c.3115G>A (p.Gly1039Ser) results in a non-conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00083 in 154310 control chromosomes (gnomAD). The observed variant frequency is approximately 1300 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. To our knowledge, no occurrence of c.3115G>A in individuals affected with Adams-Oliver Syndrome 5 and no experimental evidence demonstrating its impact on protein function have been reported. Four ClinVar submitters have assessed the variant since 2014: two classified the variant as likely benign and two as benign. Based on the evidence outlined above, the variant was classified as benign. -

NOTCH1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 07, 2024

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 13, 2017

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 02, 2021

- -

Aortic valve disease 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Mar 15, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.050
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.18
Cadd	Benign	15
Dann	Benign	0.60
DEOGEN2	Uncertain	0.43	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.011	T
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	0.81	N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.22	N
REVEL	Uncertain	0.37
Sift	Benign	0.65	T
Sift4G	Benign	0.94	T
Polyphen		0.0040	B
Vest4		0.23
MVP		0.70
MPC		0.38
ClinPred		0.0088	T
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.067

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

Other links and lift over

dbSNP: rs200207651; hg19: chr9-139403378;