rs2071287

Variant names:

• chr6-32202656-C-T
• rs2071287
• NM_004557.4:c.3232-57G>A

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.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
• Publications: 49 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=-0.85).
• BP6: Variant 6-32202656-C-T is Benign according to our data. Variant chr6-32202656-C-T is described in ClinVar as Benign. ClinVar VariationId 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.

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.3232-57G>A		intron	N/A	NP_004548.3
	NOTCH4	NR_134949.2		n.3472+1114G>A		intron	N/A
	NOTCH4	NR_134950.2		n.3370+1114G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH4	ENST00000375023.3	TSL:1 MANE Select	c.3232-57G>A		intron	N/A	ENSP00000364163.3	Q99466-1
	NOTCH4	ENST00000883244.1		c.3232-57G>A		intron	N/A	ENSP00000553303.1
	NOTCH4	ENST00000883245.1		c.3109-57G>A		intron	N/A	ENSP00000553304.1

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

African (AFR) AF: 0.373 AC: 11240 AN: 30094

American (AMR) AF: 0.394 AC: 11866 AN: 30086

Ashkenazi Jewish (ASJ) AF: 0.650 AC: 13136 AN: 20222

East Asian (EAS) AF: 0.343 AC: 12993 AN: 37856

South Asian (SAS) AF: 0.583 AC: 41553 AN: 71264

European-Finnish (FIN) AF: 0.451 AC: 20435 AN: 45332

Middle Eastern (MID) AF: 0.591 AC: 2175 AN: 3680

European-Non Finnish (NFE) AF: 0.479 AC: 499745 AN: 1042736

Other (OTH) AF: 0.475 AC: 26208 AN: 55136

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

African (AFR) AF: 0.369 AC: 15275 AN: 41450

American (AMR) AF: 0.440 AC: 6723 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.654 AC: 2269 AN: 3470

East Asian (EAS) AF: 0.344 AC: 1782 AN: 5174

South Asian (SAS) AF: 0.582 AC: 2804 AN: 4814

European-Finnish (FIN) AF: 0.458 AC: 4827 AN: 10528

Middle Eastern (MID) AF: 0.554 AC: 163 AN: 294

European-Non Finnish (NFE) AF: 0.496 AC: 33712 AN: 67970

Other (OTH) AF: 0.462 AC: 973 AN: 2108

Alfa AF: 0.489 Hom.: 66686

Bravo AF: 0.447

Asia WGS AF: 0.431 AC: 1505 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.48
DANN	Benign	0.67
PhyloP100		-1.1
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: rs2071287; hg19: chr6-32170433; COSMIC: COSV66680627;