Variant rs415929 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.522A>G(p.Thr174=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.304 in 1,612,758 control chromosomes in the GnomAD database, including 77,477 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.29 ( 6956 hom., cov: 32)

Exomes 𝑓: 0.31 ( 70521 hom. )

Consequence

NOTCH4
NM_004557.4 synonymous

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -3.33

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=-0.97).

BP6

Variant 6-32221255-T-C is Benign according to our data. Variant chr6-32221255-T-C is described in ClinVar as [Benign]. Clinvar id is 1281290.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-3.33 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.319 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
NOTCH4	NM_004557.4 linkuse as main transcript	c.522A>G	p.Thr174=	synonymous_variant	4/30	ENST00000375023.3
NOTCH4	NR_134949.2 linkuse as main transcript	n.661A>G		non_coding_transcript_exon_variant	4/30
NOTCH4	NR_134950.2 linkuse as main transcript	n.661A>G		non_coding_transcript_exon_variant	4/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOTCH4	ENST00000375023.3 linkuse as main transcript	c.522A>G	p.Thr174=	synonymous_variant	4/30	1	NM_004557.4	P1	Q99466-1
NOTCH4	ENST00000473562.1 linkuse as main transcript	n.651A>G		non_coding_transcript_exon_variant	4/11	1

Frequencies

GnomAD3 genomes

AF:

0.293

AC:

44557

AN:

151980

Hom.:

6953

Cov.:

show subpopulations

Gnomad AFR

AF:

0.212

Gnomad AMI

AF:

0.398

Gnomad AMR

AF:

0.323

Gnomad ASJ

AF:

0.507

Gnomad EAS

AF:

0.225

Gnomad SAS

AF:

0.321

Gnomad FIN

AF:

0.314

Gnomad MID

AF:

0.415

Gnomad NFE

AF:

0.322

Gnomad OTH

AF:

0.314

GnomAD3 exomes

AF:

0.310

AC:

75823

AN:

244230

Hom.:

12641

AF XY:

0.320

AC XY:

42645

AN XY:

133358

show subpopulations

Gnomad AFR exome

AF:

0.211

Gnomad AMR exome

AF:

0.265

Gnomad ASJ exome

AF:

0.507

Gnomad EAS exome

AF:

0.191

Gnomad SAS exome

AF:

0.339

Gnomad FIN exome

AF:

0.314

Gnomad NFE exome

AF:

0.331

Gnomad OTH exome

AF:

0.335

GnomAD4 exome

AF:

0.305

AC:

445874

AN:

1460660

Hom.:

70521

Cov.:

AF XY:

0.309

AC XY:

224471

AN XY:

726658

show subpopulations

Gnomad4 AFR exome

AF:

0.218

Gnomad4 AMR exome

AF:

0.269

Gnomad4 ASJ exome

AF:

0.502

Gnomad4 EAS exome

AF:

0.271

Gnomad4 SAS exome

AF:

0.335

Gnomad4 FIN exome

AF:

0.309

Gnomad4 NFE exome

AF:

0.303

Gnomad4 OTH exome

AF:

0.314

GnomAD4 genome

AF:

0.293

AC:

44562

AN:

152098

Hom.:

6956

Cov.:

AF XY:

0.294

AC XY:

21860

AN XY:

74362

show subpopulations

Gnomad4 AFR

AF:

0.212

Gnomad4 AMR

AF:

0.322

Gnomad4 ASJ

AF:

0.507

Gnomad4 EAS

AF:

0.225

Gnomad4 SAS

AF:

0.321

Gnomad4 FIN

AF:

0.314

Gnomad4 NFE

AF:

0.322

Gnomad4 OTH

AF:

0.316

Alfa

AF:

0.330

Hom.:

17148

Bravo

AF:

0.288

Asia WGS

AF:

0.347

AC:

1211

AN:

3478

EpiCase

AF:

0.350

EpiControl

AF:

0.362

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

-0.97

CADD

Benign

0.26

DANN

Benign

0.49

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