rs11574895

chr9-136510702-G-Achr9-136510702-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_017617.5(NOTCH1):c.2691C>T(p.Ala897=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0158 in 1,610,306 control chromosomes in the GnomAD database, including 218 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (13 hom., cov: 34)
  • Exomes 𝑓: 0.016 (205 hom.)
• Consequence: NOTCH1 NM_017617.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -5.84

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]

LOC124902310 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 9-136510702-G-A is Benign according to our data. Variant chr9-136510702-G-A is described in ClinVar as [Benign]. Clinvar id is 220988.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-136510702-G-A is described in Lovd as [Benign]. Variant chr9-136510702-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-5.84 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.011 (1677/152356) while in subpopulation NFE AF= 0.0177 (1205/68020). AF 95% confidence interval is 0.0169. There are 13 homozygotes in gnomad4. There are 738 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 1677 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOTCH1	NM_017617.5	c.2691C>T	p.Ala897=	synonymous_variant	17/34	ENST00000651671.1
LOC124902310	XR_007061865.1	n.507+723G>A		intron_variant, non_coding_transcript_variant
NOTCH1	XM_011518717.3	c.1968C>T	p.Ala656=	synonymous_variant	14/31
LOC124902310	XR_007061864.1	n.508-328G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOTCH1	ENST00000651671.1	c.2691C>T	p.Ala897=	synonymous_variant	17/34		NM_017617.5	P1

Frequencies

GnomAD3 genomes AF: 0.0110 AC: 1677 AN: 152238 Hom.: 13 Cov.: 34

Gnomad AFR AF: 0.00316

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.0113

Gnomad ASJ AF: 0.0107

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00809

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0177

Gnomad OTH AF: 0.0124

GnomAD3 exomes AF: 0.0122 AC: 2951 AN: 241370 Hom.: 21 AF XY: 0.0123 AC XY: 1631 AN XY: 132266

Gnomad AFR exome AF: 0.00223

Gnomad AMR exome AF: 0.00910

Gnomad ASJ exome AF: 0.00892

Gnomad EAS exome AF: 0.000169

Gnomad SAS exome AF: 0.00272

Gnomad FIN exome AF: 0.00754

Gnomad NFE exome AF: 0.0201

Gnomad OTH exome AF: 0.0171

GnomAD4 exome AF: 0.0163 AC: 23724 AN: 1457950 Hom.: 205 Cov.: 32 AF XY: 0.0159 AC XY: 11564 AN XY: 725480

Gnomad4 AFR exome AF: 0.00266

Gnomad4 AMR exome AF: 0.00933

Gnomad4 ASJ exome AF: 0.00962

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.00305

Gnomad4 FIN exome AF: 0.0103

Gnomad4 NFE exome AF: 0.0191

Gnomad4 OTH exome AF: 0.0146

GnomAD4 genome AF: 0.0110 AC: 1677 AN: 152356 Hom.: 13 Cov.: 34 AF XY: 0.00991 AC XY: 738 AN XY: 74498

Gnomad4 AFR AF: 0.00315

Gnomad4 AMR AF: 0.0112

Gnomad4 ASJ AF: 0.0107

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.00809

Gnomad4 NFE AF: 0.0177

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.0163 Hom.: 11

Bravo AF: 0.0117

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0197

EpiControl AF: 0.0204

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 27, 2016	- -
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	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 11, 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. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 14, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Adams-Oliver syndrome 5 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 20, 2015

This alteration is classified as 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. -

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
BayesDel_noAF	Benign	-0.87
Cadd	Benign	0.23
Dann	Benign	0.94

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: rs11574895; hg19: chr9-139405154; COSMIC: COSV99490110;