Variant rs2071277 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_004557.4(NOTCH4):c.3119-24A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.482 in 1,537,900 control chromosomes in the GnomAD database, including 181,533 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). There are indicators that this mutation may affect the branch point..

Frequency

Genomes: 𝑓 0.46 ( 16438 hom., cov: 30)

Exomes 𝑓: 0.48 ( 165095 hom. )

Consequence

NOTCH4
NM_004557.4 intron

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -2.07

Variant links:

Genes affected

NOTCH4 (HGNC:7884): (notch receptor 4) 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 may play a role in vascular, renal and hepatic development. Mutations in this gene may be associated with schizophrenia. Alternative splicing results in multiple transcript variants, at least one of which encodes an isoform that is proteolytically processed. [provided by RefSeq, Jan 2016]

NOTCH4 links:

NOTCH4 (HGNC:):

NOTCH4 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

This place is a probable branch point but likely benign (scored 0 / 10). Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BP6

Variant 6-32203906-T-C is Benign according to our data. Variant chr6-32203906-T-C is described in ClinVar as [Benign]. Clinvar id is 1287377.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.57 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein	UniProt
NOTCH4	NM_004557.4 linkuse as main transcript	c.3119-24A>G	intron_variant	ENST00000375023.3	NP_004548.3	Q99466-1A0A1U9X983
NOTCH4	NR_134949.2 linkuse as main transcript	n.3360-24A>G	intron_variant
NOTCH4	NR_134950.2 linkuse as main transcript	n.3258-24A>G	intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOTCH4	ENST00000375023.3 linkuse as main transcript	c.3119-24A>G		intron_variant		1	NM_004557.4	ENSP00000364163.3		Q99466-1
NOTCH4	ENST00000474612.1 linkuse as main transcript	n.35-24A>G		intron_variant		5

Frequencies

GnomAD3 genomes

AF:

0.460

AC:

69719

AN:

151616

Hom.:

16443

Cov.:

show subpopulations

Gnomad AFR

AF:

0.378

Gnomad AMI

AF:

0.576

Gnomad AMR

AF:

0.444

Gnomad ASJ

AF:

0.654

Gnomad EAS

AF:

0.404

Gnomad SAS

AF:

0.589

Gnomad FIN

AF:

0.458

Gnomad MID

AF:

0.557

Gnomad NFE

AF:

0.496

Gnomad OTH

AF:

0.466

GnomAD3 exomes

AF:

0.484

AC:

74052

AN:

153104

Hom.:

18753

AF XY:

0.500

AC XY:

40848

AN XY:

81638

show subpopulations

Gnomad AFR exome

AF:

0.375

Gnomad AMR exome

AF:

0.387

Gnomad ASJ exome

AF:

0.655

Gnomad EAS exome

AF:

0.388

Gnomad SAS exome

AF:

0.592

Gnomad FIN exome

AF:

0.456

Gnomad NFE exome

AF:

0.497

Gnomad OTH exome

AF:

0.503

GnomAD4 exome

AF:

0.484

AC:

670917

AN:

1386166

Hom.:

165095

Cov.:

AF XY:

0.490

AC XY:

335290

AN XY:

684556

show subpopulations

Gnomad4 AFR exome

AF:

0.384

Gnomad4 AMR exome

AF:

0.395

Gnomad4 ASJ exome

AF:

0.651

Gnomad4 EAS exome

AF:

0.425

Gnomad4 SAS exome

AF:

0.589

Gnomad4 FIN exome

AF:

0.450

Gnomad4 NFE exome

AF:

0.482

Gnomad4 OTH exome

AF:

0.481

GnomAD4 genome

AF:

0.460

AC:

69738

AN:

151734

Hom.:

16438

Cov.:

AF XY:

0.462

AC XY:

34252

AN XY:

74146

show subpopulations

Gnomad4 AFR

AF:

0.378

Gnomad4 AMR

AF:

0.443

Gnomad4 ASJ

AF:

0.654

Gnomad4 EAS

AF:

0.404

Gnomad4 SAS

AF:

0.588

Gnomad4 FIN

AF:

0.458

Gnomad4 NFE

AF:

0.496

Gnomad4 OTH

AF:

0.465

Alfa

AF:

0.504

Hom.:

32252

Bravo

AF:

0.452

Asia WGS

AF:

0.459

AC:

1603

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

Apr 29, 2020

This variant is associated with the following publications: (PMID: 31838262) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.014

DANN

Benign

0.64

BranchPoint Hunter

0.0

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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