Variant 6-32196022-T-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.5427A>G(p.Gln1809=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0567 in 1,598,326 control chromosomes in the GnomAD database, including 2,885 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.062 ( 343 hom., cov: 33)

Exomes 𝑓: 0.056 ( 2542 hom. )

Consequence

NOTCH4
NM_004557.4 synonymous

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.165

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=-0.61).

BP6

Variant 6-32196022-T-C is Benign according to our data. Variant chr6-32196022-T-C is described in ClinVar as [Benign]. Clinvar id is 1290716.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-0.165 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0916 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
NOTCH4	NM_004557.4 linkuse as main transcript	c.5427A>G	p.Gln1809=	synonymous_variant	30/30	ENST00000375023.3
NOTCH4	NR_134949.2 linkuse as main transcript	n.5135A>G		non_coding_transcript_exon_variant	30/30
NOTCH4	NR_134950.2 linkuse as main transcript	n.5033A>G		non_coding_transcript_exon_variant	29/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOTCH4	ENST00000375023.3 linkuse as main transcript	c.5427A>G	p.Gln1809=	synonymous_variant	30/30	1	NM_004557.4	P1	Q99466-1
NOTCH4	ENST00000474612.1 linkuse as main transcript	n.4088A>G		non_coding_transcript_exon_variant	10/10	5
NOTCH4	ENST00000491215.1 linkuse as main transcript	n.453A>G		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes

AF:

0.0616

AC:

9371

AN:

152118

Hom.:

345

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0814

Gnomad AMI

AF:

0.156

Gnomad AMR

AF:

0.0506

Gnomad ASJ

AF:

0.0456

Gnomad EAS

AF:

0.0465

Gnomad SAS

AF:

0.0993

Gnomad FIN

AF:

0.0183

Gnomad MID

AF:

0.0696

Gnomad NFE

AF:

0.0566

Gnomad OTH

AF:

0.0669

GnomAD3 exomes

AF:

0.0531

AC:

11572

AN:

217950

Hom.:

409

AF XY:

0.0569

AC XY:

6906

AN XY:

121402

show subpopulations

Gnomad AFR exome

AF:

0.0810

Gnomad AMR exome

AF:

0.0313

Gnomad ASJ exome

AF:

0.0466

Gnomad EAS exome

AF:

0.0365

Gnomad SAS exome

AF:

0.0971

Gnomad FIN exome

AF:

0.0169

Gnomad NFE exome

AF:

0.0516

Gnomad OTH exome

AF:

0.0557

GnomAD4 exome

AF:

0.0562

AC:

81251

AN:

1446090

Hom.:

2542

Cov.:

AF XY:

0.0571

AC XY:

41073

AN XY:

719706

show subpopulations

Gnomad4 AFR exome

AF:

0.0893

Gnomad4 AMR exome

AF:

0.0346

Gnomad4 ASJ exome

AF:

0.0496

Gnomad4 EAS exome

AF:

0.0539

Gnomad4 SAS exome

AF:

0.0934

Gnomad4 FIN exome

AF:

0.0212

Gnomad4 NFE exome

AF:

0.0544

Gnomad4 OTH exome

AF:

0.0593

GnomAD4 genome

AF:

0.0615

AC:

9369

AN:

152236

Hom.:

343

Cov.:

AF XY:

0.0604

AC XY:

4499

AN XY:

74436

show subpopulations

Gnomad4 AFR

AF:

0.0812

Gnomad4 AMR

AF:

0.0505

Gnomad4 ASJ

AF:

0.0456

Gnomad4 EAS

AF:

0.0468

Gnomad4 SAS

AF:

0.0989

Gnomad4 FIN

AF:

0.0183

Gnomad4 NFE

AF:

0.0566

Gnomad4 OTH

AF:

0.0662

Alfa

AF:

0.0424

Hom.:

Bravo

AF:

0.0648

Asia WGS

AF:

0.0690

AC:

240

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 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.61

CADD

Benign

9.1

DANN

Benign

0.85

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