Variant rs3134942 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_StrongBP6_ModerateBP7BA1

The NM_004557.4(NOTCH4):c.4152C>A(p.Val1384=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.128 in 1,572,234 control chromosomes in the GnomAD database, including 14,451 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.11 ( 962 hom., cov: 32)

Exomes 𝑓: 0.13 ( 13489 hom. )

Consequence

NOTCH4
NM_004557.4 synonymous

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.228

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.63).

BP6

Variant 6-32200994-G-T is Benign according to our data. Variant chr6-32200994-G-T is described in ClinVar as [Benign]. Clinvar id is 1259043.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-0.228 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.131 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
NOTCH4	NM_004557.4 linkuse as main transcript	c.4152C>A	p.Val1384=	synonymous_variant	23/30	ENST00000375023.3	NP_004548.3
NOTCH4	NR_134949.2 linkuse as main transcript	n.3869C>A		non_coding_transcript_exon_variant	23/30
NOTCH4	NR_134950.2 linkuse as main transcript	n.3767C>A		non_coding_transcript_exon_variant	22/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOTCH4	ENST00000375023.3 linkuse as main transcript	c.4152C>A	p.Val1384=	synonymous_variant	23/30	1	NM_004557.4	ENSP00000364163	P1	Q99466-1
NOTCH4	ENST00000474612.1 linkuse as main transcript	n.2813C>A		non_coding_transcript_exon_variant	3/10	5

Frequencies

GnomAD3 genomes

AF:

0.105

AC:

16028

AN:

151982

Hom.:

962

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0912

Gnomad AMI

AF:

0.0735

Gnomad AMR

AF:

0.0545

Gnomad ASJ

AF:

0.0767

Gnomad EAS

AF:

0.0281

Gnomad SAS

AF:

0.0950

Gnomad FIN

AF:

0.117

Gnomad MID

AF:

0.0541

Gnomad NFE

AF:

0.133

Gnomad OTH

AF:

0.0872

GnomAD3 exomes

AF:

0.0966

AC:

20445

AN:

211736

Hom.:

1240

AF XY:

0.0979

AC XY:

11112

AN XY:

113560

show subpopulations

Gnomad AFR exome

AF:

0.0947

Gnomad AMR exome

AF:

0.0417

Gnomad ASJ exome

AF:

0.0877

Gnomad EAS exome

AF:

0.0326

Gnomad SAS exome

AF:

0.0774

Gnomad FIN exome

AF:

0.115

Gnomad NFE exome

AF:

0.127

Gnomad OTH exome

AF:

0.0998

GnomAD4 exome

AF:

0.130

AC:

184567

AN:

1420132

Hom.:

13489

Cov.:

AF XY:

0.128

AC XY:

89933

AN XY:

702066

show subpopulations

Gnomad4 AFR exome

AF:

0.0854

Gnomad4 AMR exome

AF:

0.0436

Gnomad4 ASJ exome

AF:

0.0837

Gnomad4 EAS exome

AF:

0.0198

Gnomad4 SAS exome

AF:

0.0771

Gnomad4 FIN exome

AF:

0.115

Gnomad4 NFE exome

AF:

0.145

Gnomad4 OTH exome

AF:

0.119

GnomAD4 genome

AF:

0.105

AC:

16025

AN:

152102

Hom.:

962

Cov.:

AF XY:

0.102

AC XY:

7619

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.0911

Gnomad4 AMR

AF:

0.0542

Gnomad4 ASJ

AF:

0.0767

Gnomad4 EAS

AF:

0.0284

Gnomad4 SAS

AF:

0.0943

Gnomad4 FIN

AF:

0.117

Gnomad4 NFE

AF:

0.133

Gnomad4 OTH

AF:

0.0863

Alfa

AF:

0.119

Hom.:

1369

Bravo

AF:

0.101

Asia WGS

AF:

0.0510

AC:

177

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

May 04, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.63

CADD

Benign

1.7

DANN

Benign

0.59

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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