rs520692

Positions:

• chr6-32220863-T-C

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.815A>G​(p.Asp272Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.301 in 1,613,300 control chromosomes in the GnomAD database, including 76,302 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 0.29 (6808 hom., cov: 33)
  • Exomes 𝑓: 0.30 (69494 hom.)
• Consequence: NOTCH4 NM_004557.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.64

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=0.013173163).
• BP6: Variant 6-32220863-T-C is Benign according to our data. Variant chr6-32220863-T-C is described in ClinVar as [Benign]. Clinvar id is 1287249.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.318 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOTCH4	NM_004557.4	c.815A>G	p.Asp272Gly	missense_variant	5/30	ENST00000375023.3	NP_004548.3
NOTCH4	NR_134949.2	n.954A>G		non_coding_transcript_exon_variant	5/30
NOTCH4	NR_134950.2	n.954A>G		non_coding_transcript_exon_variant	5/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOTCH4	ENST00000375023.3	c.815A>G	p.Asp272Gly	missense_variant	5/30	1	NM_004557.4	ENSP00000364163.3
NOTCH4	ENST00000473562.1	n.944A>G		non_coding_transcript_exon_variant	5/11	1

Frequencies

GnomAD3 genomes AF: 0.290 AC: 44094 AN: 151888 Hom.: 6807 Cov.: 33

Gnomad AFR AF: 0.212

Gnomad AMI AF: 0.396

Gnomad AMR AF: 0.322

Gnomad ASJ AF: 0.506

Gnomad EAS AF: 0.164

Gnomad SAS AF: 0.316

Gnomad FIN AF: 0.313

Gnomad MID AF: 0.411

Gnomad NFE AF: 0.322

Gnomad OTH AF: 0.313

GnomAD3 exomes AF: 0.305 AC: 76557 AN: 250830 Hom.: 12707 AF XY: 0.315 AC XY: 42647 AN XY: 135542

Gnomad AFR exome AF: 0.210

Gnomad AMR exome AF: 0.264

Gnomad ASJ exome AF: 0.507

Gnomad EAS exome AF: 0.136

Gnomad SAS exome AF: 0.333

Gnomad FIN exome AF: 0.313

Gnomad NFE exome AF: 0.330

Gnomad OTH exome AF: 0.333

GnomAD4 exome AF: 0.302 AC: 441941 AN: 1461296 Hom.: 69494 Cov.: 55 AF XY: 0.306 AC XY: 222448 AN XY: 726942

Gnomad4 AFR exome AF: 0.217

Gnomad4 AMR exome AF: 0.269

Gnomad4 ASJ exome AF: 0.501

Gnomad4 EAS exome AF: 0.190

Gnomad4 SAS exome AF: 0.330

Gnomad4 FIN exome AF: 0.308

Gnomad4 NFE exome AF: 0.302

Gnomad4 OTH exome AF: 0.310

GnomAD4 genome AF: 0.290 AC: 44094 AN: 152004 Hom.: 6808 Cov.: 33 AF XY: 0.291 AC XY: 21612 AN XY: 74312

Gnomad4 AFR AF: 0.211

Gnomad4 AMR AF: 0.322

Gnomad4 ASJ AF: 0.506

Gnomad4 EAS AF: 0.164

Gnomad4 SAS AF: 0.316

Gnomad4 FIN AF: 0.313

Gnomad4 NFE AF: 0.322

Gnomad4 OTH AF: 0.315

Alfa AF: 0.326 Hom.: 13772

Bravo AF: 0.286

TwinsUK AF: 0.283 AC: 1050

ALSPAC AF: 0.282 AC: 1085

ESP6500AA AF: 0.213 AC: 937

ESP6500EA AF: 0.319 AC: 2742

ExAC AF: 0.305 AC: 37080

Asia WGS AF: 0.321 AC: 1122 AN: 3478

EpiCase AF: 0.350

EpiControl AF: 0.361

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 04, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	14
DANN	Benign	0.74
DEOGEN2	Benign	0.37	T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.40
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.48	T
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	1.9	L
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.26
Sift	Benign	0.34	T
Sift4G	Benign	0.53	T
Polyphen		0.0010	B
Vest4		0.037
MPC		0.24
ClinPred		0.0069	T
GERP RS		3.6
Varity_R		0.15
gMVP		0.66

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: rs520692; hg19: chr6-32188640; COSMIC: COSV66678393;