rs206017

Variant names:

• chr6-32208434-G-A
• rs206017
• NM_004557.4:c.2865+2318C>T

Variant summary

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

The NM_004557.4(NOTCH4):​c.2865+2318C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.601 in 152,090 control chromosomes in the GnomAD database, including 27,728 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 0.60 (27728 hom., cov: 33)
• Consequence: NOTCH4 NM_004557.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.62
• Publications: 17 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=-1.02).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.691 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOTCH4	NM_004557.4	c.2865+2318C>T		intron_variant	Intron 18 of 29	ENST00000375023.3	NP_004548.3
NOTCH4	NR_134949.2	n.3106+2318C>T		intron_variant	Intron 19 of 29
NOTCH4	NR_134950.2	n.3004+2318C>T		intron_variant	Intron 18 of 28

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOTCH4	ENST00000375023.3	c.2865+2318C>T		intron_variant	Intron 18 of 29	1	NM_004557.4	ENSP00000364163.3

Frequencies

GnomAD3 genomes AF: 0.602 AC: 91415 AN: 151972 Hom.: 27728 Cov.: 33

Gnomad AFR AF: 0.591

Gnomad AMI AF: 0.660

Gnomad AMR AF: 0.576

Gnomad ASJ AF: 0.830

Gnomad EAS AF: 0.710

Gnomad SAS AF: 0.694

Gnomad FIN AF: 0.515

Gnomad MID AF: 0.649

Gnomad NFE AF: 0.599

Gnomad OTH AF: 0.612

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

GnomAD4 genome AF: 0.601 AC: 91460 AN: 152090 Hom.: 27728 Cov.: 33 AF XY: 0.599 AC XY: 44570 AN XY: 74346

African (AFR) AF: 0.590 AC: 24486 AN: 41474

American (AMR) AF: 0.576 AC: 8803 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.830 AC: 2878 AN: 3468

East Asian (EAS) AF: 0.710 AC: 3672 AN: 5170

South Asian (SAS) AF: 0.693 AC: 3340 AN: 4818

European-Finnish (FIN) AF: 0.515 AC: 5441 AN: 10564

Middle Eastern (MID) AF: 0.653 AC: 192 AN: 294

European-Non Finnish (NFE) AF: 0.599 AC: 40751 AN: 67988

Other (OTH) AF: 0.615 AC: 1300 AN: 2114

Alfa AF: 0.609 Hom.: 36660

Bravo AF: 0.606

Asia WGS AF: 0.646 AC: 2252 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.85
DANN	Benign	0.52
PhyloP100		-1.6
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs206017; hg19: chr6-32176211;