Variant 6-32195764-A-C 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.5685T>G(p.Ser1895=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0266 in 1,610,698 control chromosomes in the GnomAD database, including 918 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.025 ( 79 hom., cov: 33)

Exomes 𝑓: 0.027 ( 839 hom. )

Consequence

NOTCH4
NM_004557.4 synonymous

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -4.43

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=-0.82).

BP6

Variant 6-32195764-A-C is Benign according to our data. Variant chr6-32195764-A-C is described in ClinVar as [Benign]. Clinvar id is 1241905.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-4.43 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0863 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.5685T>G	p.Ser1895=	synonymous_variant	30/30	ENST00000375023.3	NP_004548.3
NOTCH4	NR_134949.2 linkuse as main transcript	n.5393T>G		non_coding_transcript_exon_variant	30/30
NOTCH4	NR_134950.2 linkuse as main transcript	n.5291T>G		non_coding_transcript_exon_variant	29/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOTCH4	ENST00000375023.3 linkuse as main transcript	c.5685T>G	p.Ser1895=	synonymous_variant	30/30	1	NM_004557.4	ENSP00000364163	P1	Q99466-1
NOTCH4	ENST00000474612.1 linkuse as main transcript	n.4346T>G		non_coding_transcript_exon_variant	10/10	5
NOTCH4	ENST00000491215.1 linkuse as main transcript	n.711T>G		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes

AF:

0.0254

AC:

3865

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0167

Gnomad AMI

AF:

0.0175

Gnomad AMR

AF:

0.0131

Gnomad ASJ

AF:

0.0360

Gnomad EAS

AF:

0.0282

Gnomad SAS

AF:

0.0940

Gnomad FIN

AF:

0.0326

Gnomad MID

AF:

0.0287

Gnomad NFE

AF:

0.0268

Gnomad OTH

AF:

0.0264

GnomAD3 exomes

AF:

0.0303

AC:

7246

AN:

238836

Hom.:

186

AF XY:

0.0331

AC XY:

4349

AN XY:

131454

show subpopulations

Gnomad AFR exome

AF:

0.0171

Gnomad AMR exome

AF:

0.0128

Gnomad ASJ exome

AF:

0.0411

Gnomad EAS exome

AF:

0.0316

Gnomad SAS exome

AF:

0.0714

Gnomad FIN exome

AF:

0.0315

Gnomad NFE exome

AF:

0.0246

Gnomad OTH exome

AF:

0.0309

GnomAD4 exome

AF:

0.0268

AC:

39040

AN:

1458446

Hom.:

839

Cov.:

AF XY:

0.0284

AC XY:

20590

AN XY:

725626

show subpopulations

Gnomad4 AFR exome

AF:

0.0185

Gnomad4 AMR exome

AF:

0.0138

Gnomad4 ASJ exome

AF:

0.0397

Gnomad4 EAS exome

AF:

0.0196

Gnomad4 SAS exome

AF:

0.0748

Gnomad4 FIN exome

AF:

0.0294

Gnomad4 NFE exome

AF:

0.0236

Gnomad4 OTH exome

AF:

0.0281

GnomAD4 genome

AF:

0.0253

AC:

3858

AN:

152252

Hom.:

Cov.:

AF XY:

0.0268

AC XY:

1994

AN XY:

74434

show subpopulations

Gnomad4 AFR

AF:

0.0166

Gnomad4 AMR

AF:

0.0130

Gnomad4 ASJ

AF:

0.0360

Gnomad4 EAS

AF:

0.0285

Gnomad4 SAS

AF:

0.0935

Gnomad4 FIN

AF:

0.0326

Gnomad4 NFE

AF:

0.0268

Gnomad4 OTH

AF:

0.0261

Alfa

AF:

0.0267

Hom.:

Bravo

AF:

0.0237

Asia WGS

AF:

0.0420

AC:

146

AN:

3478

EpiCase

AF:

0.0302

EpiControl

AF:

0.0280

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 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.54

DANN

Benign

0.69

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