6-32224330-C-G

Variant names:

• chr6-32224330-C-G
• rs3134929
• ENST00000883244.1:c.-402G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000883244.1(NOTCH4):​c.-402G>C variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.267 in 152,160 control chromosomes in the GnomAD database, including 6,308 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 0.27 (6308 hom., cov: 32)
• Consequence: NOTCH4 ENST00000883244.1 upstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.631
• Publications: 13 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.421 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000883244.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH4	ENST00000883244.1		c.-402G>C		upstream_gene	N/A	ENSP00000553303.1

Frequencies

GnomAD3 genomes AF: 0.267 AC: 40613 AN: 152042 Hom.: 6305 Cov.: 32

Gnomad AFR AF: 0.406

Gnomad AMI AF: 0.257

Gnomad AMR AF: 0.256

Gnomad ASJ AF: 0.217

Gnomad EAS AF: 0.435

Gnomad SAS AF: 0.281

Gnomad FIN AF: 0.0741

Gnomad MID AF: 0.372

Gnomad NFE AF: 0.203

Gnomad OTH AF: 0.297

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

GnomAD4 genome AF: 0.267 AC: 40634 AN: 152160 Hom.: 6308 Cov.: 32 AF XY: 0.262 AC XY: 19521 AN XY: 74408

African (AFR) AF: 0.405 AC: 16812 AN: 41490

American (AMR) AF: 0.257 AC: 3927 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.217 AC: 754 AN: 3472

East Asian (EAS) AF: 0.436 AC: 2255 AN: 5174

South Asian (SAS) AF: 0.281 AC: 1351 AN: 4816

European-Finnish (FIN) AF: 0.0741 AC: 787 AN: 10618

Middle Eastern (MID) AF: 0.366 AC: 106 AN: 290

European-Non Finnish (NFE) AF: 0.203 AC: 13785 AN: 67980

Other (OTH) AF: 0.295 AC: 624 AN: 2112

Alfa AF: 0.0890 Hom.: 102

Bravo AF: 0.289

Asia WGS AF: 0.370 AC: 1283 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.9
DANN	Benign	0.80
PhyloP100		-0.63
PromoterAI		-0.032	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3134929; hg19: chr6-32192107; COSMIC: COSV66684196;