rs370606059

chr9-136497103-G-Achr9-136497103-G-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.6636C>T(p.Asp2212=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000367 in 1,611,084 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00037 (0 hom.)
• Consequence: NOTCH1 NM_017617.5 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.783

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=-0.74).
• BP6: Variant 9-136497103-G-A is Benign according to our data. Variant chr9-136497103-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 264082.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.783 with no splicing effect.
• BS2: High AC in GnomAd at 51 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOTCH1	NM_017617.5	c.6636C>T	p.Asp2212=	synonymous_variant	34/34	ENST00000651671.1
NOTCH1	XM_011518717.3	c.5913C>T	p.Asp1971=	synonymous_variant	31/31

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOTCH1	ENST00000651671.1	c.6636C>T	p.Asp2212=	synonymous_variant	34/34		NM_017617.5	P1

Frequencies

GnomAD3 genomes AF: 0.000335 AC: 51 AN: 152216 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000235 AC: 58 AN: 246360 Hom.: 0 AF XY: 0.000268 AC XY: 36 AN XY: 134484

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000551

Gnomad ASJ exome AF: 0.000101

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000306

Gnomad OTH exome AF: 0.000668

GnomAD4 exome AF: 0.000370 AC: 540 AN: 1458750 Hom.: 0 Cov.: 32 AF XY: 0.000357 AC XY: 259 AN XY: 725402

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.000671

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000430

Gnomad4 OTH exome AF: 0.000431

GnomAD4 genome AF: 0.000335 AC: 51 AN: 152334 Hom.: 0 Cov.: 33 AF XY: 0.000362 AC XY: 27 AN XY: 74486

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00157

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000323

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000164 Hom.: 0

Bravo AF: 0.000521

EpiCase AF: 0.000327

EpiControl AF: 0.000356

ClinVar

Significance: Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Nov 02, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 22, 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. -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 09, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 11, 2023	- -

Adams-Oliver syndrome 5 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 10, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -

NOTCH1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 24, 2020

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

Aortic valve disease 1 Benign:1

Likely 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	-0.74
Cadd	Benign	0.18
Dann	Benign	0.84

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: rs370606059; hg19: chr9-139391555; COSMIC: COSV53075820;