rs206015

Variant names:

• chr6-32214982-G-A
• rs206015
• NM_004557.4:c.2021+244C>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.2021+244C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.147 in 152,100 control chromosomes in the GnomAD database, including 1,930 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 0.15 (1930 hom., cov: 32)
• Consequence: NOTCH4 NM_004557.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.543
• Publications: 46 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=-0.96).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.302 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOTCH4	NM_004557.4	c.2021+244C>T		intron_variant	Intron 12 of 29	ENST00000375023.3	NP_004548.3
NOTCH4	NR_134949.2	n.2262+244C>T		intron_variant	Intron 13 of 29
NOTCH4	NR_134950.2	n.2160+244C>T		intron_variant	Intron 12 of 28

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOTCH4	ENST00000375023.3	c.2021+244C>T		intron_variant	Intron 12 of 29	1	NM_004557.4	ENSP00000364163.3

Frequencies

GnomAD3 genomes AF: 0.147 AC: 22326 AN: 151982 Hom.: 1926 Cov.: 32

Gnomad AFR AF: 0.221

Gnomad AMI AF: 0.0768

Gnomad AMR AF: 0.135

Gnomad ASJ AF: 0.177

Gnomad EAS AF: 0.315

Gnomad SAS AF: 0.113

Gnomad FIN AF: 0.0771

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.105

Gnomad OTH AF: 0.149

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

GnomAD4 genome AF: 0.147 AC: 22359 AN: 152100 Hom.: 1930 Cov.: 32 AF XY: 0.143 AC XY: 10660 AN XY: 74332

African (AFR) AF: 0.220 AC: 9143 AN: 41468

American (AMR) AF: 0.135 AC: 2069 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.177 AC: 613 AN: 3470

East Asian (EAS) AF: 0.315 AC: 1624 AN: 5162

South Asian (SAS) AF: 0.112 AC: 541 AN: 4824

European-Finnish (FIN) AF: 0.0771 AC: 817 AN: 10590

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.105 AC: 7132 AN: 67982

Other (OTH) AF: 0.152 AC: 321 AN: 2108

Alfa AF: 0.119 Hom.: 4221

Bravo AF: 0.158

Asia WGS AF: 0.196 AC: 680 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.60
DANN	Benign	0.83
PhyloP100		-0.54
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: rs206015; hg19: chr6-32182759;