rs8192591

Positions:

• chr6-32218019-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_004557.4(NOTCH4):​c.1600G>A​(p.Gly534Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0326 in 1,613,200 control chromosomes in the GnomAD database, including 1,087 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 0.022 (60 hom., cov: 32)
  • Exomes 𝑓: 0.034 (1027 hom.)
• Consequence: NOTCH4 NM_004557.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0710

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004939854).
• BP6: Variant 6-32218019-C-T is Benign according to our data. Variant chr6-32218019-C-T is described in ClinVar as [Benign]. Clinvar id is 1220553.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0523 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOTCH4	NM_004557.4	c.1600G>A	p.Gly534Ser	missense_variant	9/30	ENST00000375023.3	NP_004548.3
NOTCH4	NR_134949.2	n.1841G>A		non_coding_transcript_exon_variant	10/30
NOTCH4	NR_134950.2	n.1739G>A		non_coding_transcript_exon_variant	9/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOTCH4	ENST00000375023.3	c.1600G>A	p.Gly534Ser	missense_variant	9/30	1	NM_004557.4	ENSP00000364163.3
NOTCH4	ENST00000473562.1	n.1729G>A		non_coding_transcript_exon_variant	9/11	1

Frequencies

GnomAD3 genomes AF: 0.0223 AC: 3398 AN: 152046 Hom.: 61 Cov.: 32

Gnomad AFR AF: 0.00522

Gnomad AMI AF: 0.170

Gnomad AMR AF: 0.00931

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00984

Gnomad SAS AF: 0.0585

Gnomad FIN AF: 0.0103

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0351

Gnomad OTH AF: 0.0192

GnomAD3 exomes AF: 0.0248 AC: 6220 AN: 250774 Hom.: 131 AF XY: 0.0273 AC XY: 3699 AN XY: 135536

Gnomad AFR exome AF: 0.00580

Gnomad AMR exome AF: 0.00637

Gnomad ASJ exome AF: 0.00497

Gnomad EAS exome AF: 0.00484

Gnomad SAS exome AF: 0.0539

Gnomad FIN exome AF: 0.00976

Gnomad NFE exome AF: 0.0332

Gnomad OTH exome AF: 0.0234

GnomAD4 exome AF: 0.0336 AC: 49116 AN: 1461036 Hom.: 1027 Cov.: 31 AF XY: 0.0339 AC XY: 24641 AN XY: 726856

Gnomad4 AFR exome AF: 0.00583

Gnomad4 AMR exome AF: 0.00691

Gnomad4 ASJ exome AF: 0.00505

Gnomad4 EAS exome AF: 0.00363

Gnomad4 SAS exome AF: 0.0512

Gnomad4 FIN exome AF: 0.0121

Gnomad4 NFE exome AF: 0.0372

Gnomad4 OTH exome AF: 0.0302

GnomAD4 genome AF: 0.0223 AC: 3395 AN: 152164 Hom.: 60 Cov.: 32 AF XY: 0.0214 AC XY: 1592 AN XY: 74396

Gnomad4 AFR AF: 0.00520

Gnomad4 AMR AF: 0.00929

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.00986

Gnomad4 SAS AF: 0.0579

Gnomad4 FIN AF: 0.0103

Gnomad4 NFE AF: 0.0351

Gnomad4 OTH AF: 0.0190

Alfa AF: 0.0316 Hom.: 179

Bravo AF: 0.0211

TwinsUK AF: 0.0343 AC: 127

ALSPAC AF: 0.0374 AC: 144

ESP6500AA AF: 0.00590 AC: 26

ESP6500EA AF: 0.0360 AC: 310

ExAC AF: 0.0263 AC: 3194

Asia WGS AF: 0.0190 AC: 65 AN: 3478

EpiCase AF: 0.0359

EpiControl AF: 0.0340

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 05, 2021

This variant is associated with the following publications: (PMID: 33134369) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	7.3
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.043	T
MetaRNN	Benign	0.0049	T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	0.17	N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.27
Sift	Benign	0.040	D
Sift4G	Benign	0.18	T
Polyphen		0.85	P
Vest4		0.055
MPC		0.38
ClinPred		0.022	T
GERP RS		2.4
Varity_R		0.050
gMVP		0.64

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

Other links and lift over

dbSNP: rs8192591; hg19: chr6-32185796; COSMIC: COSV66678933; COSMIC: COSV66678933;