rs394657

Positions:

• chr6-32219246-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004557.4(NOTCH4):​c.1510+346T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.399 in 151,956 control chromosomes in the GnomAD database, including 12,710 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.40 (12710 hom., cov: 32)
• Consequence: NOTCH4 NM_004557.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.435

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.451 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOTCH4	NM_004557.4	c.1510+346T>C		intron_variant		ENST00000375023.3	NP_004548.3
NOTCH4	NR_134949.2	n.1649+346T>C		intron_variant
NOTCH4	NR_134950.2	n.1649+346T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOTCH4	ENST00000375023.3	c.1510+346T>C		intron_variant		1	NM_004557.4	ENSP00000364163.3
NOTCH4	ENST00000473562.1	n.1639+346T>C		intron_variant		1

Frequencies

GnomAD3 genomes AF: 0.399 AC: 60657 AN: 151838 Hom.: 12716 Cov.: 32

Gnomad AFR AF: 0.298

Gnomad AMI AF: 0.464

Gnomad AMR AF: 0.404

Gnomad ASJ AF: 0.569

Gnomad EAS AF: 0.210

Gnomad SAS AF: 0.467

Gnomad FIN AF: 0.427

Gnomad MID AF: 0.500

Gnomad NFE AF: 0.455

Gnomad OTH AF: 0.410

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.399 AC: 60661 AN: 151956 Hom.: 12710 Cov.: 32 AF XY: 0.398 AC XY: 29578 AN XY: 74252

Gnomad4 AFR AF: 0.298

Gnomad4 AMR AF: 0.404

Gnomad4 ASJ AF: 0.569

Gnomad4 EAS AF: 0.210

Gnomad4 SAS AF: 0.466

Gnomad4 FIN AF: 0.427

Gnomad4 NFE AF: 0.455

Gnomad4 OTH AF: 0.411

Alfa AF: 0.461 Hom.: 27641

Bravo AF: 0.392

Asia WGS AF: 0.370 AC: 1295 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.3
DANN	Benign	0.74

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: rs394657; hg19: chr6-32187023;