Variant 6-32222629-A-G 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.333T>C(p.Gly111=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.396 in 1,605,374 control chromosomes in the GnomAD database, including 129,327 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.40 ( 12343 hom., cov: 32)

Exomes 𝑓: 0.40 ( 116984 hom. )

Consequence

NOTCH4
NM_004557.4 synonymous

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -2.87

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=-0.95).

BP6

Variant 6-32222629-A-G is Benign according to our data. Variant chr6-32222629-A-G is described in ClinVar as [Benign]. Clinvar id is 1293220.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-2.87 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.52 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
NOTCH4	NM_004557.4 linkuse as main transcript	c.333T>C	p.Gly111=	synonymous_variant	3/30	ENST00000375023.3	NP_004548.3
NOTCH4	NR_134949.2 linkuse as main transcript	n.472T>C		non_coding_transcript_exon_variant	3/30
NOTCH4	NR_134950.2 linkuse as main transcript	n.472T>C		non_coding_transcript_exon_variant	3/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOTCH4	ENST00000375023.3 linkuse as main transcript	c.333T>C	p.Gly111=	synonymous_variant	3/30	1	NM_004557.4	ENSP00000364163	P1	Q99466-1
NOTCH4	ENST00000473562.1 linkuse as main transcript	n.462T>C		non_coding_transcript_exon_variant	3/11	1

Frequencies

GnomAD3 genomes

AF:

0.396

AC:

60110

AN:

151912

Hom.:

12340

Cov.:

show subpopulations

Gnomad AFR

AF:

0.463

Gnomad AMI

AF:

0.415

Gnomad AMR

AF:

0.363

Gnomad ASJ

AF:

0.449

Gnomad EAS

AF:

0.536

Gnomad SAS

AF:

0.486

Gnomad FIN

AF:

0.239

Gnomad MID

AF:

0.370

Gnomad NFE

AF:

0.366

Gnomad OTH

AF:

0.408

GnomAD3 exomes

AF:

0.376

AC:

91467

AN:

243264

Hom.:

18121

AF XY:

0.380

AC XY:

50144

AN XY:

131912

show subpopulations

Gnomad AFR exome

AF:

0.468

Gnomad AMR exome

AF:

0.335

Gnomad ASJ exome

AF:

0.442

Gnomad EAS exome

AF:

0.498

Gnomad SAS exome

AF:

0.462

Gnomad FIN exome

AF:

0.234

Gnomad NFE exome

AF:

0.354

Gnomad OTH exome

AF:

0.379

GnomAD4 exome

AF:

0.396

AC:

575338

AN:

1453344

Hom.:

116984

Cov.:

AF XY:

0.397

AC XY:

287158

AN XY:

723178

show subpopulations

Gnomad4 AFR exome

AF:

0.469

Gnomad4 AMR exome

AF:

0.343

Gnomad4 ASJ exome

AF:

0.452

Gnomad4 EAS exome

AF:

0.526

Gnomad4 SAS exome

AF:

0.464

Gnomad4 FIN exome

AF:

0.235

Gnomad4 NFE exome

AF:

0.391

Gnomad4 OTH exome

AF:

0.416

GnomAD4 genome

AF:

0.396

AC:

60151

AN:

152030

Hom.:

12343

Cov.:

AF XY:

0.391

AC XY:

29025

AN XY:

74304

show subpopulations

Gnomad4 AFR

AF:

0.462

Gnomad4 AMR

AF:

0.363

Gnomad4 ASJ

AF:

0.449

Gnomad4 EAS

AF:

0.536

Gnomad4 SAS

AF:

0.485

Gnomad4 FIN

AF:

0.239

Gnomad4 NFE

AF:

0.366

Gnomad4 OTH

AF:

0.407

Alfa

AF:

0.370

Hom.:

14382

Bravo

AF:

0.413

Asia WGS

AF:

0.431

AC:

1502

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 04, 2021

This variant is associated with the following publications: (PMID: 31705708, 12589427) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.95

CADD

Benign

0.38

DANN

Benign

0.50

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