Variant 6-32197022-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_ModerateBP6_ModerateBP7BS2

The NM_004557.4(NOTCH4):c.5103G>A(p.Gly1701=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0011 in 1,612,940 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0011 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 11 hom. )

Consequence

NOTCH4
NM_004557.4 synonymous

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.318

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.46).

BP6

Variant 6-32197022-C-T is Benign according to our data. Variant chr6-32197022-C-T is described in ClinVar as [Benign]. Clinvar id is 735623.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-0.318 with no splicing effect.

BS2

High AC in GnomAd4 at 162 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
NOTCH4	NM_004557.4 linkuse as main transcript	c.5103G>A	p.Gly1701=	synonymous_variant	28/30	ENST00000375023.3
NOTCH4	NR_134949.2 linkuse as main transcript	n.4811G>A		non_coding_transcript_exon_variant	28/30
NOTCH4	NR_134950.2 linkuse as main transcript	n.4709G>A		non_coding_transcript_exon_variant	27/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOTCH4	ENST00000375023.3 linkuse as main transcript	c.5103G>A	p.Gly1701=	synonymous_variant	28/30	1	NM_004557.4	P1	Q99466-1
NOTCH4	ENST00000474612.1 linkuse as main transcript	n.3764G>A		non_coding_transcript_exon_variant	8/10	5
NOTCH4	ENST00000491215.1 linkuse as main transcript			upstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.00106

AC:

162

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000523

Gnomad ASJ

AF:

0.00866

Gnomad EAS

AF:

0.00636

Gnomad SAS

AF:

0.00580

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000721

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00192

AC:

473

AN:

246562

Hom.:

AF XY:

0.00216

AC XY:

290

AN XY:

134374

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000319

Gnomad ASJ exome

AF:

0.00792

Gnomad EAS exome

AF:

0.00498

Gnomad SAS exome

AF:

0.00523

Gnomad FIN exome

AF:

0.0000928

Gnomad NFE exome

AF:

0.00101

Gnomad OTH exome

AF:

0.00313

GnomAD4 exome

AF:

0.00110

AC:

1614

AN:

1460668

Hom.:

Cov.:

AF XY:

0.00128

AC XY:

931

AN XY:

726648

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000492

Gnomad4 ASJ exome

AF:

0.00861

Gnomad4 EAS exome

AF:

0.00277

Gnomad4 SAS exome

AF:

0.00566

Gnomad4 FIN exome

AF:

0.0000766

Gnomad4 NFE exome

AF:

0.000527

Gnomad4 OTH exome

AF:

0.00220

GnomAD4 genome

AF:

0.00106

AC:

162

AN:

152272

Hom.:

Cov.:

AF XY:

0.00111

AC XY:

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.000523

Gnomad4 ASJ

AF:

0.00866

Gnomad4 EAS

AF:

0.00637

Gnomad4 SAS

AF:

0.00580

Gnomad4 FIN

AF:

0.0000943

Gnomad4 NFE

AF:

0.000721

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00160

Hom.:

Bravo

AF:

0.00102

Asia WGS

AF:

0.00549

AC:

AN:

3478

EpiCase

AF:

0.00174

EpiControl

AF:

0.00130

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

Labcorp Genetics (formerly Invitae), Labcorp

Apr 24, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.46

CADD

Benign

8.2

DANN

Benign

0.91

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