Variant rs2071278 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.4757-73T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.15 in 1,365,258 control chromosomes in the GnomAD database, including 16,531 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.13 ( 1428 hom., cov: 33)

Exomes 𝑓: 0.15 ( 15103 hom. )

Consequence

NOTCH4
NM_004557.4 intron

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.267

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:

NOTCH4 (HGNC:):

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=-0.91).

BP6

Variant 6-32197667-A-G is Benign according to our data. Variant chr6-32197667-A-G is described in ClinVar as [Benign]. Clinvar id is 1179245.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.192 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein	UniProt
NOTCH4	NM_004557.4 linkuse as main transcript	c.4757-73T>C	intron_variant	ENST00000375023.3	NP_004548.3	Q99466-1A0A1U9X983
NOTCH4	NR_134949.2 linkuse as main transcript	n.4465-73T>C	intron_variant
NOTCH4	NR_134950.2 linkuse as main transcript	n.4363-73T>C	intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOTCH4	ENST00000375023.3 linkuse as main transcript	c.4757-73T>C		intron_variant		1	NM_004557.4	ENSP00000364163.3		Q99466-1
NOTCH4	ENST00000474612.1 linkuse as main transcript	n.3418-73T>C		intron_variant		5

Frequencies

GnomAD3 genomes

AF:

0.130

AC:

19773

AN:

152140

Hom.:

1431

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0962

Gnomad AMI

AF:

0.0954

Gnomad AMR

AF:

0.0936

Gnomad ASJ

AF:

0.137

Gnomad EAS

AF:

0.203

Gnomad SAS

AF:

0.162

Gnomad FIN

AF:

0.142

Gnomad MID

AF:

0.0791

Gnomad NFE

AF:

0.150

Gnomad OTH

AF:

0.115

GnomAD4 exome

AF:

0.153

AC:

185325

AN:

1212998

Hom.:

15103

AF XY:

0.152

AC XY:

90635

AN XY:

598204

show subpopulations

Gnomad4 AFR exome

AF:

0.0877

Gnomad4 AMR exome

AF:

0.0962

Gnomad4 ASJ exome

AF:

0.141

Gnomad4 EAS exome

AF:

0.185

Gnomad4 SAS exome

AF:

0.122

Gnomad4 FIN exome

AF:

0.138

Gnomad4 NFE exome

AF:

0.158

Gnomad4 OTH exome

AF:

0.155

GnomAD4 genome

AF:

0.130

AC:

19767

AN:

152260

Hom.:

1428

Cov.:

AF XY:

0.129

AC XY:

9619

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.0960

Gnomad4 AMR

AF:

0.0933

Gnomad4 ASJ

AF:

0.137

Gnomad4 EAS

AF:

0.203

Gnomad4 SAS

AF:

0.161

Gnomad4 FIN

AF:

0.142

Gnomad4 NFE

AF:

0.150

Gnomad4 OTH

AF:

0.115

Alfa

AF:

0.151

Hom.:

2522

Bravo

AF:

0.124

Asia WGS

AF:

0.143

AC:

497

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 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

4.2

DANN

Benign

0.61

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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