Variant 6-32219828-A-G details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_004557.4(NOTCH4):c.1316-42T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.557 in 1,541,746 control chromosomes in the GnomAD database, including 240,083 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.54 ( 22650 hom., cov: 30)

Exomes 𝑓: 0.56 ( 217433 hom. )

Consequence

NOTCH4
NM_004557.4 intron

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.747

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 -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 6-32219828-A-G is Benign according to our data. Variant chr6-32219828-A-G is described in ClinVar as [Benign]. Clinvar id is 1252692.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.677 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein	UniProt
NOTCH4	NM_004557.4 link	c.1316-42T>C	intron_variant	ENST00000375023.3	NP_004548.3	Q99466-1A0A1U9X983
NOTCH4	NR_134949.2 link	n.1455-42T>C	intron_variant
NOTCH4	NR_134950.2 link	n.1455-42T>C	intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOTCH4	ENST00000375023.3 link	c.1316-42T>C		intron_variant		1	NM_004557.4	ENSP00000364163.3		Q99466-1
NOTCH4	ENST00000473562.1 link	n.1445-42T>C		intron_variant		1

Frequencies

GnomAD3 genomes

AF:

0.544

AC:

82499

AN:

151662

Hom.:

22650

Cov.:

show subpopulations

Gnomad AFR

AF:

0.519

Gnomad AMI

AF:

0.608

Gnomad AMR

AF:

0.519

Gnomad ASJ

AF:

0.710

Gnomad EAS

AF:

0.697

Gnomad SAS

AF:

0.609

Gnomad FIN

AF:

0.492

Gnomad MID

AF:

0.557

Gnomad NFE

AF:

0.547

Gnomad OTH

AF:

0.552

GnomAD3 exomes

AF:

0.566

AC:

114788

AN:

202632

Hom.:

32362

AF XY:

0.571

AC XY:

62428

AN XY:

109402

show subpopulations

Gnomad AFR exome

AF:

0.530

Gnomad AMR exome

AF:

0.522

Gnomad ASJ exome

AF:

0.716

Gnomad EAS exome

AF:

0.678

Gnomad SAS exome

AF:

0.594

Gnomad FIN exome

AF:

0.499

Gnomad NFE exome

AF:

0.558

Gnomad OTH exome

AF:

0.562

GnomAD4 exome

AF:

0.559

AC:

776426

AN:

1389966

Hom.:

217433

Cov.:

AF XY:

0.560

AC XY:

386834

AN XY:

690590

show subpopulations

Gnomad4 AFR exome

AF:

0.525

Gnomad4 AMR exome

AF:

0.516

Gnomad4 ASJ exome

AF:

0.710

Gnomad4 EAS exome

AF:

0.695

Gnomad4 SAS exome

AF:

0.592

Gnomad4 FIN exome

AF:

0.485

Gnomad4 NFE exome

AF:

0.553

Gnomad4 OTH exome

AF:

0.561

GnomAD4 genome

AF:

0.544

AC:

82543

AN:

151780

Hom.:

22650

Cov.:

AF XY:

0.541

AC XY:

40122

AN XY:

74156

show subpopulations

Gnomad4 AFR

AF:

0.519

Gnomad4 AMR

AF:

0.519

Gnomad4 ASJ

AF:

0.710

Gnomad4 EAS

AF:

0.696

Gnomad4 SAS

AF:

0.609

Gnomad4 FIN

AF:

0.492

Gnomad4 NFE

AF:

0.547

Gnomad4 OTH

AF:

0.556

Alfa

AF:

0.557

Hom.:

19467

Bravo

AF:

0.546

Asia WGS

AF:

0.602

AC:

2093

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 13, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

2.8

DANN

Benign

0.64

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