ENST00000473562.1:n.2367A>G

Variant names:

• chr6-32216568-T-C
• rs404860
• ENST00000473562.1:n.2367A>G

Variant summary

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

The ENST00000473562.1(NOTCH4):​n.2367A>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.19 in 339,092 control chromosomes in the GnomAD database, including 7,245 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 0.21 (3782 hom., cov: 33)
  • Exomes 𝑓: 0.17 (3463 hom.)
• Consequence: NOTCH4 ENST00000473562.1 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.812
• Publications: 78 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=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.423 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000473562.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH4	NM_004557.4	MANE Select	c.1861+377A>G		intron	N/A	NP_004548.3
	NOTCH4	NR_134949.2		n.2102+377A>G		intron	N/A
	NOTCH4	NR_134950.2		n.2000+377A>G		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH4	ENST00000473562.1	TSL:1	n.2367A>G		non_coding_transcript_exon	Exon 11 of 11
	NOTCH4	ENST00000375023.3	TSL:1 MANE Select	c.1861+377A>G		intron	N/A	ENSP00000364163.3

Frequencies

GnomAD3 genomes AF: 0.209 AC: 31868 AN: 152154 Hom.: 3778 Cov.: 33

Gnomad AFR AF: 0.296

Gnomad AMI AF: 0.127

Gnomad AMR AF: 0.189

Gnomad ASJ AF: 0.224

Gnomad EAS AF: 0.438

Gnomad SAS AF: 0.186

Gnomad FIN AF: 0.110

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.162

Gnomad OTH AF: 0.213

GnomAD4 exome AF: 0.173 AC: 32405 AN: 186820 Hom.: 3463 Cov.: 0 AF XY: 0.173 AC XY: 17245 AN XY: 99910

African (AFR) AF: 0.277 AC: 1545 AN: 5570

American (AMR) AF: 0.194 AC: 1460 AN: 7530

Ashkenazi Jewish (ASJ) AF: 0.228 AC: 1168 AN: 5116

East Asian (EAS) AF: 0.431 AC: 3543 AN: 8222

South Asian (SAS) AF: 0.161 AC: 4855 AN: 30126

European-Finnish (FIN) AF: 0.0980 AC: 845 AN: 8626

Middle Eastern (MID) AF: 0.183 AC: 135 AN: 738

European-Non Finnish (NFE) AF: 0.154 AC: 17147 AN: 111124

Other (OTH) AF: 0.175 AC: 1707 AN: 9768

GnomAD4 genome AF: 0.210 AC: 31909 AN: 152272 Hom.: 3782 Cov.: 33 AF XY: 0.206 AC XY: 15325 AN XY: 74462

African (AFR) AF: 0.296 AC: 12275 AN: 41532

American (AMR) AF: 0.189 AC: 2892 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.224 AC: 776 AN: 3472

East Asian (EAS) AF: 0.438 AC: 2267 AN: 5180

South Asian (SAS) AF: 0.186 AC: 899 AN: 4826

European-Finnish (FIN) AF: 0.110 AC: 1164 AN: 10616

Middle Eastern (MID) AF: 0.173 AC: 51 AN: 294

European-Non Finnish (NFE) AF: 0.162 AC: 11012 AN: 68022

Other (OTH) AF: 0.216 AC: 457 AN: 2116

Alfa AF: 0.177 Hom.: 9943

Bravo AF: 0.223

Asia WGS AF: 0.263 AC: 912 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.24
DANN	Benign	0.70
PhyloP100		-0.81
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs404860; hg19: chr6-32184345;