Variant chr9-136507052-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_017617.5(NOTCH1):c.3644-79C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.525 in 1,555,742 control chromosomes in the GnomAD database, including 219,805 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.57 ( 25862 hom., cov: 36)

Exomes 𝑓: 0.52 ( 193943 hom. )

Consequence

NOTCH1
NM_017617.5 intron

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -3.05

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BP6

Variant 9-136507052-G-A is Benign according to our data. Variant chr9-136507052-G-A is described in ClinVar as [Benign]. Clinvar id is 678563.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.859 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOTCH1	NM_017617.5 linkuse as main transcript	c.3644-79C>T		intron_variant		ENST00000651671.1
NOTCH1	XM_011518717.3 linkuse as main transcript	c.2921-79C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOTCH1	ENST00000651671.1 linkuse as main transcript	c.3644-79C>T		intron_variant			NM_017617.5	P1

Frequencies

GnomAD3 genomes

AF:

0.573

AC:

87215

AN:

152098

Hom.:

25836

Cov.:

show subpopulations

Gnomad AFR

AF:

0.674

Gnomad AMI

AF:

0.372

Gnomad AMR

AF:

0.601

Gnomad ASJ

AF:

0.615

Gnomad EAS

AF:

0.880

Gnomad SAS

AF:

0.636

Gnomad FIN

AF:

0.454

Gnomad MID

AF:

0.522

Gnomad NFE

AF:

0.498

Gnomad OTH

AF:

0.561

GnomAD4 exome

AF:

0.519

AC:

729078

AN:

1403524

Hom.:

193943

AF XY:

0.523

AC XY:

363343

AN XY:

694184

show subpopulations

Gnomad4 AFR exome

AF:

0.674

Gnomad4 AMR exome

AF:

0.661

Gnomad4 ASJ exome

AF:

0.608

Gnomad4 EAS exome

AF:

0.837

Gnomad4 SAS exome

AF:

0.638

Gnomad4 FIN exome

AF:

0.457

Gnomad4 NFE exome

AF:

0.489

Gnomad4 OTH exome

AF:

0.553

GnomAD4 genome

AF:

0.573

AC:

87296

AN:

152218

Hom.:

25862

Cov.:

AF XY:

0.579

AC XY:

43077

AN XY:

74428

show subpopulations

Gnomad4 AFR

AF:

0.674

Gnomad4 AMR

AF:

0.601

Gnomad4 ASJ

AF:

0.615

Gnomad4 EAS

AF:

0.881

Gnomad4 SAS

AF:

0.636

Gnomad4 FIN

AF:

0.454

Gnomad4 NFE

AF:

0.498

Gnomad4 OTH

AF:

0.564

Alfa

AF:

0.516

Hom.:

22259

Bravo

AF:

0.591

Asia WGS

AF:

0.756

AC:

2627

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 18, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.71

DANN

Benign

0.60

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over