6-32218019-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_004557.4(NOTCH4):c.1600G>A(p.Gly534Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0326 in 1,613,200 control chromosomes in the GnomAD database, including 1,087 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.022 ( 60 hom., cov: 32)

Exomes 𝑓: 0.034 ( 1027 hom. )

Consequence

NOTCH4
NM_004557.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.0710

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004939854).

BP6

Variant 6-32218019-C-T is Benign according to our data. Variant chr6-32218019-C-T is described in ClinVar as [Benign]. Clinvar id is 1220553.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0523 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOTCH4	NM_004557.4 link	c.1600G>A	p.Gly534Ser	missense_variant	Exon 9 of 30	ENST00000375023.3	NP_004548.3	Q99466-1A0A1U9X983
NOTCH4	NR_134949.2 link	n.1841G>A		non_coding_transcript_exon_variant	Exon 10 of 30
NOTCH4	NR_134950.2 link	n.1739G>A		non_coding_transcript_exon_variant	Exon 9 of 29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOTCH4	ENST00000375023.3 link	c.1600G>A	p.Gly534Ser	missense_variant	Exon 9 of 30	1	NM_004557.4	ENSP00000364163.3		Q99466-1
NOTCH4	ENST00000473562.1 link	n.1729G>A		non_coding_transcript_exon_variant	Exon 9 of 11	1

Frequencies

GnomAD3 genomes

AF:

0.0223

AC:

3398

AN:

152046

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00522

Gnomad AMI

AF:

0.170

Gnomad AMR

AF:

0.00931

Gnomad ASJ

AF:

0.00346

Gnomad EAS

AF:

0.00984

Gnomad SAS

AF:

0.0585

Gnomad FIN

AF:

0.0103

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0351

Gnomad OTH

AF:

0.0192

GnomAD3 exomes

AF:

0.0248

AC:

6220

AN:

250774

Hom.:

131

AF XY:

0.0273

AC XY:

3699

AN XY:

135536

show subpopulations

Gnomad AFR exome

AF:

0.00580

Gnomad AMR exome

AF:

0.00637

Gnomad ASJ exome

AF:

0.00497

Gnomad EAS exome

AF:

0.00484

Gnomad SAS exome

AF:

0.0539

Gnomad FIN exome

AF:

0.00976

Gnomad NFE exome

AF:

0.0332

Gnomad OTH exome

AF:

0.0234

GnomAD4 exome

AF:

0.0336

AC:

49116

AN:

1461036

Hom.:

1027

Cov.:

AF XY:

0.0339

AC XY:

24641

AN XY:

726856

show subpopulations

Gnomad4 AFR exome

AF:

0.00583

Gnomad4 AMR exome

AF:

0.00691

Gnomad4 ASJ exome

AF:

0.00505

Gnomad4 EAS exome

AF:

0.00363

Gnomad4 SAS exome

AF:

0.0512

Gnomad4 FIN exome

AF:

0.0121

Gnomad4 NFE exome

AF:

0.0372

Gnomad4 OTH exome

AF:

0.0302

GnomAD4 genome

AF:

0.0223

AC:

3395

AN:

152164

Hom.:

Cov.:

AF XY:

0.0214

AC XY:

1592

AN XY:

74396

show subpopulations

Gnomad4 AFR

AF:

0.00520

Gnomad4 AMR

AF:

0.00929

Gnomad4 ASJ

AF:

0.00346

Gnomad4 EAS

AF:

0.00986

Gnomad4 SAS

AF:

0.0579

Gnomad4 FIN

AF:

0.0103

Gnomad4 NFE

AF:

0.0351

Gnomad4 OTH

AF:

0.0190

Alfa

AF:

0.0316

Hom.:

179

Bravo

AF:

0.0211

TwinsUK

AF:

0.0343

AC:

127

ALSPAC

AF:

0.0374

AC:

144

ESP6500AA

AF:

0.00590

AC:

ESP6500EA

AF:

0.0360

AC:

310

ExAC

AF:

0.0263

AC:

3194

Asia WGS

AF:

0.0190

AC:

AN:

3478

EpiCase

AF:

0.0359

EpiControl

AF:

0.0340

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

May 05, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 33134369) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.51

CADD

Benign

7.3

DANN

Uncertain

1.0

DEOGEN2

Benign

0.19

Eigen

Benign

-0.44

Eigen_PC

Benign

-0.54

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.043

MetaRNN

Benign

0.0049

MetaSVM

Benign

-0.59

MutationAssessor

Benign

0.17

PrimateAI

Benign

0.39

PROVEAN

Benign

-1.1

REVEL

Benign

0.27

Sift

Benign

0.040

Sift4G

Benign

0.18

Polyphen

0.85

Vest4

0.055

MPC

0.38

ClinPred

0.022

GERP RS

2.4

Varity_R

0.050

gMVP

0.64

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