rs3132956

Positions:

• chr6-32211661-G-A

Variant summary

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

The NM_004557.4(NOTCH4):​c.2681-725C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.105 in 151,970 control chromosomes in the GnomAD database, including 965 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 0.11 (965 hom., cov: 31)
• Consequence: NOTCH4 NM_004557.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.832

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.131 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOTCH4	NM_004557.4	c.2681-725C>T		intron_variant		ENST00000375023.3
NOTCH4	NR_134949.2	n.2922-725C>T		intron_variant, non_coding_transcript_variant
NOTCH4	NR_134950.2	n.2820-725C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOTCH4	ENST00000375023.3	c.2681-725C>T		intron_variant		1	NM_004557.4	P1
NOTCH4	ENST00000465528.1	n.554-725C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.106 AC: 16030 AN: 151852 Hom.: 965 Cov.: 31

Gnomad AFR AF: 0.0914

Gnomad AMI AF: 0.0735

Gnomad AMR AF: 0.0543

Gnomad ASJ AF: 0.0767

Gnomad EAS AF: 0.0288

Gnomad SAS AF: 0.0948

Gnomad FIN AF: 0.116

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.133

Gnomad OTH AF: 0.0902

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

GnomAD4 genome AF: 0.105 AC: 16027 AN: 151970 Hom.: 965 Cov.: 31 AF XY: 0.102 AC XY: 7598 AN XY: 74278

Gnomad4 AFR AF: 0.0913

Gnomad4 AMR AF: 0.0540

Gnomad4 ASJ AF: 0.0767

Gnomad4 EAS AF: 0.0291

Gnomad4 SAS AF: 0.0940

Gnomad4 FIN AF: 0.116

Gnomad4 NFE AF: 0.133

Gnomad4 OTH AF: 0.0893

Alfa AF: 0.122 Hom.: 900

Bravo AF: 0.101

Asia WGS AF: 0.0540 AC: 187 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	5.6
DANN	Benign	0.18

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: rs3132956; hg19: chr6-32179438;