ENST00000473562.1:n.2138C>T

Variant names:

• chr6-32216797-G-A
• rs384247
• ENST00000473562.1:n.2138C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000473562.1(NOTCH4):​n.2138C>T 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 0.183 in 986,634 control chromosomes in the GnomAD database, including 18,612 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.21 (3631 hom., cov: 33)
  • Exomes 𝑓: 0.18 (14981 hom.)
• Consequence: NOTCH4 ENST00000473562.1 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.31
• Publications: 25 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 6-32216797-G-A is Benign according to our data. Variant chr6-32216797-G-A is described in ClinVar as Benign. ClinVar VariationId is 1248031.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.363 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+148C>T		intron	N/A	NP_004548.3
	NOTCH4	NR_134949.2		n.2102+148C>T		intron	N/A
	NOTCH4	NR_134950.2		n.2000+148C>T		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH4	ENST00000473562.1	TSL:1	n.2138C>T		non_coding_transcript_exon	Exon 11 of 11
	NOTCH4	ENST00000375023.3	TSL:1 MANE Select	c.1861+148C>T		intron	N/A	ENSP00000364163.3

Frequencies

GnomAD3 genomes AF: 0.207 AC: 31523 AN: 152076 Hom.: 3627 Cov.: 33

Gnomad AFR AF: 0.296

Gnomad AMI AF: 0.127

Gnomad AMR AF: 0.189

Gnomad ASJ AF: 0.223

Gnomad EAS AF: 0.378

Gnomad SAS AF: 0.182

Gnomad FIN AF: 0.110

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.162

Gnomad OTH AF: 0.211

GnomAD4 exome AF: 0.178 AC: 148691 AN: 834442 Hom.: 14981 Cov.: 11 AF XY: 0.176 AC XY: 76829 AN XY: 436222

African (AFR) AF: 0.294 AC: 6198 AN: 21054

American (AMR) AF: 0.210 AC: 8364 AN: 39888

Ashkenazi Jewish (ASJ) AF: 0.227 AC: 4718 AN: 20754

East Asian (EAS) AF: 0.388 AC: 14005 AN: 36080

South Asian (SAS) AF: 0.165 AC: 11321 AN: 68788

European-Finnish (FIN) AF: 0.106 AC: 4859 AN: 45868

Middle Eastern (MID) AF: 0.157 AC: 706 AN: 4504

European-Non Finnish (NFE) AF: 0.163 AC: 91064 AN: 557780

Other (OTH) AF: 0.188 AC: 7456 AN: 39726

GnomAD4 genome AF: 0.207 AC: 31562 AN: 152192 Hom.: 3631 Cov.: 33 AF XY: 0.203 AC XY: 15121 AN XY: 74408

African (AFR) AF: 0.296 AC: 12268 AN: 41482

American (AMR) AF: 0.189 AC: 2892 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.223 AC: 775 AN: 3468

East Asian (EAS) AF: 0.377 AC: 1954 AN: 5184

South Asian (SAS) AF: 0.181 AC: 875 AN: 4822

European-Finnish (FIN) AF: 0.110 AC: 1163 AN: 10596

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

European-Non Finnish (NFE) AF: 0.162 AC: 11016 AN: 68018

Other (OTH) AF: 0.214 AC: 452 AN: 2112

Alfa AF: 0.178 Hom.: 5249

Bravo AF: 0.221

Asia WGS AF: 0.238 AC: 827 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

May 13, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	7.8
DANN	Benign	0.81
PhyloP100		1.3
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: rs384247; hg19: chr6-32184574; COSMIC: COSV107495996; COSMIC: COSV107495996;