rs206016

Variant names:

• chr6-32213405-G-A
• rs206016
• NM_004557.4:c.2321-153C>T

Variant summary

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

The NM_004557.4(NOTCH4):​c.2321-153C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.144 in 151,718 control chromosomes in the GnomAD database, including 1,860 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.14 (1860 hom., cov: 31)
• Consequence: NOTCH4 NM_004557.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.84
• Publications: 29 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=-1.01).
• BP6: Variant 6-32213405-G-A is Benign according to our data. Variant chr6-32213405-G-A is described in ClinVar as Benign. ClinVar VariationId is 1271072.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.292 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOTCH4	NM_004557.4	c.2321-153C>T		intron_variant	Intron 14 of 29	ENST00000375023.3	NP_004548.3
NOTCH4	NR_134949.2	n.2562-153C>T		intron_variant	Intron 15 of 29
NOTCH4	NR_134950.2	n.2460-153C>T		intron_variant	Intron 14 of 28

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOTCH4	ENST00000375023.3	c.2321-153C>T		intron_variant	Intron 14 of 29	1	NM_004557.4	ENSP00000364163.3
NOTCH4	ENST00000465528.1	n.282-153C>T		intron_variant	Intron 2 of 4	5

Frequencies

GnomAD3 genomes AF: 0.144 AC: 21843 AN: 151598 Hom.: 1856 Cov.: 31

Gnomad AFR AF: 0.221

Gnomad AMI AF: 0.0752

Gnomad AMR AF: 0.134

Gnomad ASJ AF: 0.177

Gnomad EAS AF: 0.305

Gnomad SAS AF: 0.109

Gnomad FIN AF: 0.0568

Gnomad MID AF: 0.0892

Gnomad NFE AF: 0.103

Gnomad OTH AF: 0.147

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

GnomAD4 genome AF: 0.144 AC: 21875 AN: 151718 Hom.: 1860 Cov.: 31 AF XY: 0.140 AC XY: 10383 AN XY: 74142

African (AFR) AF: 0.221 AC: 9138 AN: 41298

American (AMR) AF: 0.135 AC: 2055 AN: 15246

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

East Asian (EAS) AF: 0.304 AC: 1567 AN: 5154

South Asian (SAS) AF: 0.108 AC: 520 AN: 4816

European-Finnish (FIN) AF: 0.0568 AC: 598 AN: 10520

Middle Eastern (MID) AF: 0.0993 AC: 29 AN: 292

European-Non Finnish (NFE) AF: 0.103 AC: 6970 AN: 67908

Other (OTH) AF: 0.150 AC: 317 AN: 2110

Alfa AF: 0.118 Hom.: 3005

Bravo AF: 0.156

Asia WGS AF: 0.191 AC: 661 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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.16
DANN	Benign	0.88
PhyloP100		-2.8
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: rs206016; hg19: chr6-32181182; COSMIC: COSV107495995; COSMIC: COSV107495995;