rs35980907

chr9-136503225-C-Achr9-136503225-C-Gchr9-136503225-C-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_017617.5(NOTCH1):c.5124G>T(p.Ser1708=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00673 in 1,612,792 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S1708S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0051 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0069 (44 hom.)
• Consequence: NOTCH1 NM_017617.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.851

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 9-136503225-C-A is Benign according to our data. Variant chr9-136503225-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 241147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-136503225-C-A is described in Lovd as [Likely_benign]. Variant chr9-136503225-C-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.851 with no splicing effect.
• BS2: High AC in GnomAd at 780 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOTCH1	NM_017617.5	c.5124G>T	p.Ser1708=	synonymous_variant	27/34	ENST00000651671.1
NOTCH1	XM_011518717.3	c.4401G>T	p.Ser1467=	synonymous_variant	24/31

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOTCH1	ENST00000651671.1	c.5124G>T	p.Ser1708=	synonymous_variant	27/34		NM_017617.5	P1

Frequencies

GnomAD3 genomes AF: 0.00513 AC: 780 AN: 152184 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00152

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00386

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00358

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00870

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00460 AC: 1139 AN: 247722 Hom.: 6 AF XY: 0.00476 AC XY: 643 AN XY: 134970

Gnomad AFR exome AF: 0.00104

Gnomad AMR exome AF: 0.00241

Gnomad ASJ exome AF: 0.00300

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.000425

Gnomad FIN exome AF: 0.00403

Gnomad NFE exome AF: 0.00774

Gnomad OTH exome AF: 0.00699

GnomAD4 exome AF: 0.00689 AC: 10067 AN: 1460490 Hom.: 44 Cov.: 31 AF XY: 0.00666 AC XY: 4839 AN XY: 726552

Gnomad4 AFR exome AF: 0.00131

Gnomad4 AMR exome AF: 0.00275

Gnomad4 ASJ exome AF: 0.00337

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000429

Gnomad4 FIN exome AF: 0.00368

Gnomad4 NFE exome AF: 0.00834

Gnomad4 OTH exome AF: 0.00508

GnomAD4 genome AF: 0.00512 AC: 780 AN: 152302 Hom.: 2 Cov.: 33 AF XY: 0.00471 AC XY: 351 AN XY: 74474

Gnomad4 AFR AF: 0.00152

Gnomad4 AMR AF: 0.00386

Gnomad4 ASJ AF: 0.00519

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00358

Gnomad4 NFE AF: 0.00870

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00566 Hom.: 1

Bravo AF: 0.00468

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00720

EpiControl AF: 0.00788

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 21, 2023	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 03, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	NOTCH1: BP4, BP7, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Familial thoracic aortic aneurysm and aortic dissection Benign:2

Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jan 04, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 03, 2015	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. -

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 30, 2024	- -

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

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 02, 2021

- -

Aortic valve disease 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Mar 15, 2022

- -

Connective tissue disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Nov 01, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
Cadd	Benign	0.40
Dann	Benign	0.86
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs35980907; hg19: chr9-139397677; COSMIC: COSV53054324;