rs8192585

Positions:

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_004557.4(NOTCH4):c.731C>T(p.Ser244Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0411 in 1,611,614 control chromosomes in the GnomAD database, including 1,522 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.035 ( 117 hom., cov: 33)

Exomes 𝑓: 0.042 ( 1405 hom. )

Consequence

NOTCH4
NM_004557.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.69

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 (MetaRNN=0.0051605105).

BP6

Variant 6-32221046-G-A is Benign according to our data. Variant chr6-32221046-G-A is described in ClinVar as [Benign]. Clinvar id is 1232512.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0349 (5320/152280) while in subpopulation NFE AF= 0.0456 (3099/67990). AF 95% confidence interval is 0.0442. There are 117 homozygotes in gnomad4. There are 2640 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 5320 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
NOTCH4	NM_004557.4 linkuse as main transcript	c.731C>T	p.Ser244Leu	missense_variant	4/30	ENST00000375023.3
NOTCH4	NR_134949.2 linkuse as main transcript	n.870C>T		non_coding_transcript_exon_variant	4/30
NOTCH4	NR_134950.2 linkuse as main transcript	n.870C>T		non_coding_transcript_exon_variant	4/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOTCH4	ENST00000375023.3 linkuse as main transcript	c.731C>T	p.Ser244Leu	missense_variant	4/30	1	NM_004557.4	P1	Q99466-1
NOTCH4	ENST00000473562.1 linkuse as main transcript	n.860C>T		non_coding_transcript_exon_variant	4/11	1

Frequencies

GnomAD3 genomes

AF:

0.0349

AC:

5312

AN:

152162

Hom.:

116

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0208

Gnomad AMI

AF:

0.0132

Gnomad AMR

AF:

0.0285

Gnomad ASJ

AF:

0.00894

Gnomad EAS

AF:

0.0168

Gnomad SAS

AF:

0.0290

Gnomad FIN

AF:

0.0547

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0456

Gnomad OTH

AF:

0.0287

GnomAD3 exomes

AF:

0.0357

AC:

8771

AN:

245824

Hom.:

198

AF XY:

0.0356

AC XY:

4770

AN XY:

133854

show subpopulations

Gnomad AFR exome

AF:

0.0187

Gnomad AMR exome

AF:

0.0283

Gnomad ASJ exome

AF:

0.00924

Gnomad EAS exome

AF:

0.0179

Gnomad SAS exome

AF:

0.0294

Gnomad FIN exome

AF:

0.0554

Gnomad NFE exome

AF:

0.0438

Gnomad OTH exome

AF:

0.0311

GnomAD4 exome

AF:

0.0417

AC:

60837

AN:

1459334

Hom.:

1405

Cov.:

AF XY:

0.0415

AC XY:

30155

AN XY:

725760

show subpopulations

Gnomad4 AFR exome

AF:

0.0189

Gnomad4 AMR exome

AF:

0.0278

Gnomad4 ASJ exome

AF:

0.00961

Gnomad4 EAS exome

AF:

0.0308

Gnomad4 SAS exome

AF:

0.0300

Gnomad4 FIN exome

AF:

0.0568

Gnomad4 NFE exome

AF:

0.0448

Gnomad4 OTH exome

AF:

0.0335

GnomAD4 genome

AF:

0.0349

AC:

5320

AN:

152280

Hom.:

117

Cov.:

AF XY:

0.0355

AC XY:

2640

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.0208

Gnomad4 AMR

AF:

0.0288

Gnomad4 ASJ

AF:

0.00894

Gnomad4 EAS

AF:

0.0168

Gnomad4 SAS

AF:

0.0288

Gnomad4 FIN

AF:

0.0547

Gnomad4 NFE

AF:

0.0456

Gnomad4 OTH

AF:

0.0284

Alfa

AF:

0.0389

Hom.:

272

Bravo

AF:

0.0308

TwinsUK

AF:

0.0515

AC:

191

ALSPAC

AF:

0.0407

AC:

157

ESP6500AA

AF:

0.0172

AC:

ESP6500EA

AF:

0.0382

AC:

207

ExAC

AF:

0.0351

AC:

4217

Asia WGS

AF:

0.0250

AC:

AN:

3476

EpiCase

AF:

0.0415

EpiControl

AF:

0.0420

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 04, 2021

This variant is associated with the following publications: (PMID: 19197363) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.51

CADD

Benign

0.011

DANN

Benign

0.54

DEOGEN2

Benign

0.18

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.015

LIST_S2

Benign

0.16

MetaRNN

Benign

0.0052

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-1.8

MutationTaster

Benign

1.0

PrimateAI

Benign

0.31

PROVEAN

Benign

0.91

REVEL

Benign

0.22

Sift

Benign

0.68

Sift4G

Benign

1.0

Polyphen

0.0020

Vest4

0.044

MPC

0.16

ClinPred

0.011

GERP RS

-6.9

Varity_R

0.036

gMVP

0.32

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