rs2256594

Positions:

• chr6-32219095-A-G
• chr6-32219095-A-T

Variant summary

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

The NM_004557.4(NOTCH4):​c.1510+497T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.202 in 151,980 control chromosomes in the GnomAD database, including 3,499 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 0.20 (3499 hom., cov: 32)
• Consequence: NOTCH4 NM_004557.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.608

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=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.357 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOTCH4	NM_004557.4	c.1510+497T>C		intron_variant		ENST00000375023.3	NP_004548.3
NOTCH4	NR_134949.2	n.1649+497T>C		intron_variant
NOTCH4	NR_134950.2	n.1649+497T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOTCH4	ENST00000375023.3	c.1510+497T>C		intron_variant		1	NM_004557.4	ENSP00000364163.3
NOTCH4	ENST00000473562.1	n.1639+497T>C		intron_variant		1

Frequencies

GnomAD3 genomes AF: 0.202 AC: 30625 AN: 151862 Hom.: 3496 Cov.: 32

Gnomad AFR AF: 0.295

Gnomad AMI AF: 0.126

Gnomad AMR AF: 0.177

Gnomad ASJ AF: 0.221

Gnomad EAS AF: 0.372

Gnomad SAS AF: 0.178

Gnomad FIN AF: 0.0838

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.158

Gnomad OTH AF: 0.206

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

GnomAD4 genome AF: 0.202 AC: 30667 AN: 151980 Hom.: 3499 Cov.: 32 AF XY: 0.197 AC XY: 14652 AN XY: 74302

Gnomad4 AFR AF: 0.294

Gnomad4 AMR AF: 0.177

Gnomad4 ASJ AF: 0.221

Gnomad4 EAS AF: 0.371

Gnomad4 SAS AF: 0.178

Gnomad4 FIN AF: 0.0838

Gnomad4 NFE AF: 0.158

Gnomad4 OTH AF: 0.208

Alfa AF: 0.168 Hom.: 3639

Bravo AF: 0.217

Asia WGS AF: 0.223 AC: 774 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.6
DANN	Benign	0.83

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: rs2256594; hg19: chr6-32186872;