6-32222251-A-G

Variant names:

• chr6-32222251-A-G
• rs3132946
• NM_004557.4:c.451+260T>C

Variant summary

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

The NM_004557.4(NOTCH4):​c.451+260T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.914 in 152,294 control chromosomes in the GnomAD database, including 63,832 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 0.91 (63832 hom., cov: 33)
• Consequence: NOTCH4 NM_004557.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0530
• Publications: 54 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=-0.95).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.973 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004557.4. 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
	NOTCH4	NM_004557.4	MANE Select	c.451+260T>C		intron	N/A	NP_004548.3
	NOTCH4	NR_134949.2		n.590+260T>C		intron	N/A
	NOTCH4	NR_134950.2		n.590+260T>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH4	ENST00000375023.3	TSL:1 MANE Select	c.451+260T>C		intron	N/A	ENSP00000364163.3	Q99466-1
	NOTCH4	ENST00000473562.1	TSL:1	n.580+260T>C		intron	N/A
	NOTCH4	ENST00000883244.1		c.451+260T>C		intron	N/A	ENSP00000553303.1

Frequencies

GnomAD3 genomes AF: 0.914 AC: 139066 AN: 152176 Hom.: 63769 Cov.: 33

Gnomad AFR AF: 0.974

Gnomad AMI AF: 0.928

Gnomad AMR AF: 0.935

Gnomad ASJ AF: 0.969

Gnomad EAS AF: 0.996

Gnomad SAS AF: 0.974

Gnomad FIN AF: 0.875

Gnomad MID AF: 0.953

Gnomad NFE AF: 0.864

Gnomad OTH AF: 0.935

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

GnomAD4 genome AF: 0.914 AC: 139187 AN: 152294 Hom.: 63832 Cov.: 33 AF XY: 0.915 AC XY: 68157 AN XY: 74468

African (AFR) AF: 0.974 AC: 40480 AN: 41562

American (AMR) AF: 0.935 AC: 14314 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.969 AC: 3365 AN: 3472

East Asian (EAS) AF: 0.996 AC: 5162 AN: 5184

South Asian (SAS) AF: 0.974 AC: 4704 AN: 4830

European-Finnish (FIN) AF: 0.875 AC: 9280 AN: 10600

Middle Eastern (MID) AF: 0.949 AC: 279 AN: 294

European-Non Finnish (NFE) AF: 0.864 AC: 58782 AN: 68018

Other (OTH) AF: 0.936 AC: 1975 AN: 2110

Alfa AF: 0.887 Hom.: 259418

Bravo AF: 0.922

Asia WGS AF: 0.982 AC: 3414 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	7.3
DANN	Benign	0.64
PhyloP100		0.053
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: rs3132946; hg19: chr6-32190028;