Variant 6-32197042-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_004557.4(NOTCH4):c.5083G>A(p.Asp1695Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000183 in 1,612,752 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0011 ( 1 hom., cov: 32)

Exomes 𝑓: 0.000088 ( 0 hom. )

Consequence

NOTCH4
NM_004557.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 3.81

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 -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.015914172).

BP6

Variant 6-32197042-C-T is Benign according to our data. Variant chr6-32197042-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 709047.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 166 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
NOTCH4	NM_004557.4 linkuse as main transcript	c.5083G>A	p.Asp1695Asn	missense_variant	28/30	ENST00000375023.3
NOTCH4	NR_134949.2 linkuse as main transcript	n.4791G>A		non_coding_transcript_exon_variant	28/30
NOTCH4	NR_134950.2 linkuse as main transcript	n.4689G>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.5083G>A	p.Asp1695Asn	missense_variant	28/30	1	NM_004557.4	P1	Q99466-1
NOTCH4	ENST00000474612.1 linkuse as main transcript	n.3744G>A		non_coding_transcript_exon_variant	8/10	5

Frequencies

GnomAD3 genomes

AF:

0.00109

AC:

166

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00372

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.000252

AC:

AN:

246348

Hom.:

AF XY:

0.000209

AC XY:

AN XY:

134260

show subpopulations

Gnomad AFR exome

AF:

0.00357

Gnomad AMR exome

AF:

0.000232

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000883

AC:

129

AN:

1460576

Hom.:

Cov.:

AF XY:

0.0000716

AC XY:

AN XY:

726610

show subpopulations

Gnomad4 AFR exome

AF:

0.00299

Gnomad4 AMR exome

AF:

0.000246

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.000232

GnomAD4 genome

AF:

0.00109

AC:

166

AN:

152176

Hom.:

Cov.:

AF XY:

0.000968

AC XY:

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.00372

Gnomad4 AMR

AF:

0.000458

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00239

Alfa

AF:

0.000213

Hom.:

Bravo

AF:

0.00122

ESP6500AA

AF:

0.00265

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000253

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jul 23, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.25

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

Eigen

Uncertain

0.31

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.79

M_CAP

Benign

0.034

MetaRNN

Benign

0.016

MetaSVM

Benign

-0.72

MutationAssessor

Benign

-0.57

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-4.2

REVEL

Benign

0.26

Sift

Benign

0.030

Sift4G

Benign

0.068

Polyphen

0.48

Vest4

0.18

MVP

0.84

MPC

0.64

ClinPred

0.085

GERP RS

4.5

Varity_R

0.14

gMVP

0.73

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