Variant rs1044506 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.2967A>C(p.Gly989Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.883 in 1,613,012 control chromosomes in the GnomAD database, including 630,810 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.91 ( 63823 hom., cov: 32)

Exomes 𝑓: 0.88 ( 566987 hom. )

Consequence

NOTCH4
NM_004557.4 synonymous

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.337

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 -15 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.51).

BP6

Variant 6-32204288-T-G is Benign according to our data. Variant chr6-32204288-T-G is described in ClinVar as [Benign]. Clinvar id is 1277124.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=0.337 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.973 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOTCH4	NM_004557.4 linkuse as main transcript	c.2967A>C	p.Gly989Gly	synonymous_variant	19/30	ENST00000375023.3	NP_004548.3	Q99466-1A0A1U9X983
NOTCH4	NR_134949.2 linkuse as main transcript	n.3208A>C		non_coding_transcript_exon_variant	20/30
NOTCH4	NR_134950.2 linkuse as main transcript	n.3106A>C		non_coding_transcript_exon_variant	19/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOTCH4	ENST00000375023.3 linkuse as main transcript	c.2967A>C	p.Gly989Gly	synonymous_variant	19/30	1	NM_004557.4	ENSP00000364163.3		Q99466-1

Frequencies

GnomAD3 genomes

AF:

0.914

AC:

139054

AN:

152146

Hom.:

63760

Cov.:

show subpopulations

Gnomad AFR

AF:

0.973

Gnomad AMI

AF:

0.928

Gnomad AMR

AF:

0.935

Gnomad ASJ

AF:

0.970

Gnomad EAS

AF:

0.995

Gnomad SAS

AF:

0.973

Gnomad FIN

AF:

0.882

Gnomad MID

AF:

0.953

Gnomad NFE

AF:

0.864

Gnomad OTH

AF:

0.936

GnomAD3 exomes

AF:

0.916

AC:

225770

AN:

246552

Hom.:

103817

AF XY:

0.917

AC XY:

123234

AN XY:

134396

show subpopulations

Gnomad AFR exome

AF:

0.978

Gnomad AMR exome

AF:

0.955

Gnomad ASJ exome

AF:

0.974

Gnomad EAS exome

AF:

0.998

Gnomad SAS exome

AF:

0.976

Gnomad FIN exome

AF:

0.871

Gnomad NFE exome

AF:

0.869

Gnomad OTH exome

AF:

0.903

GnomAD4 exome

AF:

0.880

AC:

1284913

AN:

1460748

Hom.:

566987

Cov.:

AF XY:

0.883

AC XY:

641574

AN XY:

726694

show subpopulations

Gnomad4 AFR exome

AF:

0.978

Gnomad4 AMR exome

AF:

0.953

Gnomad4 ASJ exome

AF:

0.971

Gnomad4 EAS exome

AF:

0.999

Gnomad4 SAS exome

AF:

0.976

Gnomad4 FIN exome

AF:

0.866

Gnomad4 NFE exome

AF:

0.860

Gnomad4 OTH exome

AF:

0.890

GnomAD4 genome

AF:

0.914

AC:

139175

AN:

152264

Hom.:

63823

Cov.:

AF XY:

0.916

AC XY:

68187

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.973

Gnomad4 AMR

AF:

0.935

Gnomad4 ASJ

AF:

0.970

Gnomad4 EAS

AF:

0.995

Gnomad4 SAS

AF:

0.974

Gnomad4 FIN

AF:

0.882

Gnomad4 NFE

AF:

0.864

Gnomad4 OTH

AF:

0.937

Alfa

AF:

0.889

Hom.:

38923

Bravo

AF:

0.921

Asia WGS

AF:

0.981

AC:

3413

AN:

3478

EpiCase

AF:

0.882

EpiControl

AF:

0.889

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

-0.51

CADD

Benign

7.7

DANN

Benign

0.74

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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