Variant chr6-32198607-C-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.4617+42G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0689 in 1,610,484 control chromosomes in the GnomAD database, including 4,633 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.056 ( 339 hom., cov: 32)

Exomes 𝑓: 0.070 ( 4294 hom. )

Consequence

NOTCH4
NM_004557.4 intron

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.22

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=-0.85).

BP6

Variant 6-32198607-C-G is Benign according to our data. Variant chr6-32198607-C-G is described in ClinVar as [Benign]. Clinvar id is 1232677.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.187 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein	UniProt
NOTCH4	NM_004557.4 linkuse as main transcript	c.4617+42G>C	intron_variant	ENST00000375023.3	NP_004548.3	Q99466-1A0A1U9X983
NOTCH4	NR_134949.2 linkuse as main transcript	n.4326-48G>C	intron_variant
NOTCH4	NR_134950.2 linkuse as main transcript	n.4224-48G>C	intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOTCH4	ENST00000375023.3 linkuse as main transcript	c.4617+42G>C		intron_variant		1	NM_004557.4	ENSP00000364163.3		Q99466-1
NOTCH4	ENST00000474612.1 linkuse as main transcript	n.3278+42G>C		intron_variant		5

Frequencies

GnomAD3 genomes

AF:

0.0563

AC:

8560

AN:

152024

Hom.:

336

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0365

Gnomad AMI

AF:

0.0417

Gnomad AMR

AF:

0.0574

Gnomad ASJ

AF:

0.148

Gnomad EAS

AF:

0.197

Gnomad SAS

AF:

0.0703

Gnomad FIN

AF:

0.0275

Gnomad MID

AF:

0.0475

Gnomad NFE

AF:

0.0562

Gnomad OTH

AF:

0.0656

GnomAD3 exomes

AF:

0.0697

AC:

17014

AN:

244020

Hom.:

775

AF XY:

0.0676

AC XY:

8991

AN XY:

132964

show subpopulations

Gnomad AFR exome

AF:

0.0354

Gnomad AMR exome

AF:

0.0716

Gnomad ASJ exome

AF:

0.156

Gnomad EAS exome

AF:

0.177

Gnomad SAS exome

AF:

0.0603

Gnomad FIN exome

AF:

0.0292

Gnomad NFE exome

AF:

0.0586

Gnomad OTH exome

AF:

0.0746

GnomAD4 exome

AF:

0.0702

AC:

102427

AN:

1458342

Hom.:

4294

Cov.:

AF XY:

0.0696

AC XY:

50477

AN XY:

725282

show subpopulations

Gnomad4 AFR exome

AF:

0.0358

Gnomad4 AMR exome

AF:

0.0695

Gnomad4 ASJ exome

AF:

0.151

Gnomad4 EAS exome

AF:

0.209

Gnomad4 SAS exome

AF:

0.0613

Gnomad4 FIN exome

AF:

0.0292

Gnomad4 NFE exome

AF:

0.0668

Gnomad4 OTH exome

AF:

0.0763

GnomAD4 genome

AF:

0.0563

AC:

8572

AN:

152142

Hom.:

339

Cov.:

AF XY:

0.0557

AC XY:

4147

AN XY:

74390

show subpopulations

Gnomad4 AFR

AF:

0.0365

Gnomad4 AMR

AF:

0.0579

Gnomad4 ASJ

AF:

0.148

Gnomad4 EAS

AF:

0.197

Gnomad4 SAS

AF:

0.0702

Gnomad4 FIN

AF:

0.0275

Gnomad4 NFE

AF:

0.0561

Gnomad4 OTH

AF:

0.0678

Alfa

AF:

0.0702

Hom.:

293

Bravo

AF:

0.0597

Asia WGS

AF:

0.0950

AC:

329

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 15, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

1.7

DANN

Benign

0.57

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.20

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.20

Position offset: 42

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