Variant chr6-32195887-C-T 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.5562G>A(p.Gly1854=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0092 in 1,590,470 control chromosomes in the GnomAD database, including 786 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0063 ( 36 hom., cov: 33)

Exomes 𝑓: 0.0095 ( 750 hom. )

Consequence

NOTCH4
NM_004557.4 synonymous

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.132

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=-0.48).

BP6

Variant 6-32195887-C-T is Benign according to our data. Variant chr6-32195887-C-T is described in ClinVar as [Benign]. Clinvar id is 1277130.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=0.132 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0793 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
NOTCH4	NM_004557.4 linkuse as main transcript	c.5562G>A	p.Gly1854=	synonymous_variant	30/30	ENST00000375023.3
NOTCH4	NR_134949.2 linkuse as main transcript	n.5270G>A		non_coding_transcript_exon_variant	30/30
NOTCH4	NR_134950.2 linkuse as main transcript	n.5168G>A		non_coding_transcript_exon_variant	29/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOTCH4	ENST00000375023.3 linkuse as main transcript	c.5562G>A	p.Gly1854=	synonymous_variant	30/30	1	NM_004557.4	P1	Q99466-1
NOTCH4	ENST00000474612.1 linkuse as main transcript	n.4223G>A		non_coding_transcript_exon_variant	10/10	5
NOTCH4	ENST00000491215.1 linkuse as main transcript	n.588G>A		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes

AF:

0.00629

AC:

958

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00273

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00464

Gnomad ASJ

AF:

0.00864

Gnomad EAS

AF:

0.00538

Gnomad SAS

AF:

0.0855

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.00392

Gnomad OTH

AF:

0.0105

GnomAD3 exomes

AF:

0.0191

AC:

3941

AN:

206292

Hom.:

252

AF XY:

0.0259

AC XY:

2982

AN XY:

115298

show subpopulations

Gnomad AFR exome

AF:

0.00282

Gnomad AMR exome

AF:

0.00472

Gnomad ASJ exome

AF:

0.00632

Gnomad EAS exome

AF:

0.00362

Gnomad SAS exome

AF:

0.110

Gnomad FIN exome

AF:

0.000486

Gnomad NFE exome

AF:

0.00448

Gnomad OTH exome

AF:

0.0107

GnomAD4 exome

AF:

0.00951

AC:

13671

AN:

1438112

Hom.:

750

Cov.:

AF XY:

0.0133

AC XY:

9496

AN XY:

715236

show subpopulations

Gnomad4 AFR exome

AF:

0.00226

Gnomad4 AMR exome

AF:

0.00452

Gnomad4 ASJ exome

AF:

0.00750

Gnomad4 EAS exome

AF:

0.00216

Gnomad4 SAS exome

AF:

0.106

Gnomad4 FIN exome

AF:

0.000397

Gnomad4 NFE exome

AF:

0.00288

Gnomad4 OTH exome

AF:

0.00873

GnomAD4 genome

AF:

0.00628

AC:

957

AN:

152358

Hom.:

Cov.:

AF XY:

0.00805

AC XY:

600

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.00272

Gnomad4 AMR

AF:

0.00464

Gnomad4 ASJ

AF:

0.00864

Gnomad4 EAS

AF:

0.00520

Gnomad4 SAS

AF:

0.0862

Gnomad4 FIN

AF:

0.000282

Gnomad4 NFE

AF:

0.00392

Gnomad4 OTH

AF:

0.00993

Alfa

AF:

0.00585

Hom.:

Bravo

AF:

0.00435

Asia WGS

AF:

0.0200

AC:

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 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.48

CADD

Benign

8.5

DANN

Uncertain

0.97

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