rs2071287

Positions:

• chr6-32202656-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_004557.4(NOTCH4):​c.3232-57G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.476 in 1,488,404 control chromosomes in the GnomAD database, including 171,857 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.45 (16176 hom., cov: 31)
  • Exomes 𝑓: 0.48 (155681 hom.)
• Consequence: NOTCH4 NM_004557.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.07

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

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 6-32202656-C-T is Benign according to our data. Variant chr6-32202656-C-T is described in ClinVar as [Benign]. Clinvar id is 1260628.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.564 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOTCH4	NM_004557.4	c.3232-57G>A		intron_variant		ENST00000375023.3
NOTCH4	NR_134949.2	n.3472+1114G>A		intron_variant, non_coding_transcript_variant
NOTCH4	NR_134950.2	n.3370+1114G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOTCH4	ENST00000375023.3	c.3232-57G>A		intron_variant		1	NM_004557.4	P1
NOTCH4	ENST00000474612.1	n.1261G>A		non_coding_transcript_exon_variant	2/10	5

Frequencies

GnomAD3 genomes AF: 0.455 AC: 69043 AN: 151880 Hom.: 16185 Cov.: 31

Gnomad AFR AF: 0.369

Gnomad AMI AF: 0.577

Gnomad AMR AF: 0.440

Gnomad ASJ AF: 0.654

Gnomad EAS AF: 0.344

Gnomad SAS AF: 0.583

Gnomad FIN AF: 0.458

Gnomad MID AF: 0.560

Gnomad NFE AF: 0.496

Gnomad OTH AF: 0.462

GnomAD4 exome AF: 0.478 AC: 639351 AN: 1336406 Hom.: 155681 Cov.: 24 AF XY: 0.483 AC XY: 315680 AN XY: 653398

Gnomad4 AFR exome AF: 0.373

Gnomad4 AMR exome AF: 0.394

Gnomad4 ASJ exome AF: 0.650

Gnomad4 EAS exome AF: 0.343

Gnomad4 SAS exome AF: 0.583

Gnomad4 FIN exome AF: 0.451

Gnomad4 NFE exome AF: 0.479

Gnomad4 OTH exome AF: 0.475

GnomAD4 genome AF: 0.454 AC: 69054 AN: 151998 Hom.: 16176 Cov.: 31 AF XY: 0.456 AC XY: 33900 AN XY: 74310

Gnomad4 AFR AF: 0.369

Gnomad4 AMR AF: 0.440

Gnomad4 ASJ AF: 0.654

Gnomad4 EAS AF: 0.344

Gnomad4 SAS AF: 0.582

Gnomad4 FIN AF: 0.458

Gnomad4 NFE AF: 0.496

Gnomad4 OTH AF: 0.462

Alfa AF: 0.499 Hom.: 26634

Bravo AF: 0.447

Asia WGS AF: 0.431 AC: 1505 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 13, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.48
DANN	Benign	0.67

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

Publications

LitVar

Other links and lift over

dbSNP: rs2071287; hg19: chr6-32170433; COSMIC: COSV66680627;