6-32212119-C-T

Variant names:

• chr6-32212119-C-T
• rs2071286
• NM_004557.4:c.2680+355G>A

Variant summary

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

The NM_004557.4(NOTCH4):​c.2680+355G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.172 in 152,012 control chromosomes in the GnomAD database, including 2,893 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 0.17 (2893 hom., cov: 31)
• Consequence: NOTCH4 NM_004557.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.00
• Publications: 58 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=-0.89).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.213 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOTCH4	NM_004557.4	c.2680+355G>A		intron_variant	Intron 17 of 29	ENST00000375023.3	NP_004548.3
NOTCH4	NR_134949.2	n.2921+355G>A		intron_variant	Intron 18 of 29
NOTCH4	NR_134950.2	n.2819+355G>A		intron_variant	Intron 17 of 28

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOTCH4	ENST00000375023.3	c.2680+355G>A		intron_variant	Intron 17 of 29	1	NM_004557.4	ENSP00000364163.3
NOTCH4	ENST00000465528.1	n.553+355G>A		intron_variant	Intron 4 of 4	5

Frequencies

GnomAD3 genomes AF: 0.172 AC: 26138 AN: 151894 Hom.: 2891 Cov.: 31

Gnomad AFR AF: 0.0419

Gnomad AMI AF: 0.279

Gnomad AMR AF: 0.219

Gnomad ASJ AF: 0.382

Gnomad EAS AF: 0.134

Gnomad SAS AF: 0.192

Gnomad FIN AF: 0.256

Gnomad MID AF: 0.271

Gnomad NFE AF: 0.216

Gnomad OTH AF: 0.185

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

GnomAD4 genome AF: 0.172 AC: 26147 AN: 152012 Hom.: 2893 Cov.: 31 AF XY: 0.176 AC XY: 13065 AN XY: 74312

African (AFR) AF: 0.0418 AC: 1734 AN: 41482

American (AMR) AF: 0.219 AC: 3343 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.382 AC: 1326 AN: 3468

East Asian (EAS) AF: 0.135 AC: 696 AN: 5164

South Asian (SAS) AF: 0.192 AC: 926 AN: 4812

European-Finnish (FIN) AF: 0.256 AC: 2700 AN: 10564

Middle Eastern (MID) AF: 0.281 AC: 82 AN: 292

European-Non Finnish (NFE) AF: 0.216 AC: 14690 AN: 67950

Other (OTH) AF: 0.189 AC: 397 AN: 2104

Alfa AF: 0.207 Hom.: 14688

Bravo AF: 0.163

Asia WGS AF: 0.184 AC: 642 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.7
DANN	Benign	0.79
PhyloP100		-1.0
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: rs2071286; hg19: chr6-32179896;