6-32203906-T-C

Variant names:

• chr6-32203906-T-C
• rs2071277
• NM_004557.4:c.3119-24A>G

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.3119-24A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.482 in 1,537,900 control chromosomes in the GnomAD database, including 181,533 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.46 (16438 hom., cov: 30)
  • Exomes 𝑓: 0.48 (165095 hom.)
• Consequence: NOTCH4 NM_004557.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.07
• Publications: 69 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: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 0 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 6-32203906-T-C is Benign according to our data. Variant chr6-32203906-T-C is described in ClinVar as Benign. ClinVar VariationId is 1287377.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.57 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOTCH4	NM_004557.4	c.3119-24A>G		intron_variant	Intron 19 of 29	ENST00000375023.3	NP_004548.3
NOTCH4	NR_134949.2	n.3360-24A>G		intron_variant	Intron 20 of 29
NOTCH4	NR_134950.2	n.3258-24A>G		intron_variant	Intron 19 of 28

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOTCH4	ENST00000375023.3	c.3119-24A>G		intron_variant	Intron 19 of 29	1	NM_004557.4	ENSP00000364163.3
NOTCH4	ENST00000474612.1	n.35-24A>G		intron_variant	Intron 1 of 9	5

Frequencies

GnomAD3 genomes AF: 0.460 AC: 69719 AN: 151616 Hom.: 16443 Cov.: 30

Gnomad AFR AF: 0.378

Gnomad AMI AF: 0.576

Gnomad AMR AF: 0.444

Gnomad ASJ AF: 0.654

Gnomad EAS AF: 0.404

Gnomad SAS AF: 0.589

Gnomad FIN AF: 0.458

Gnomad MID AF: 0.557

Gnomad NFE AF: 0.496

Gnomad OTH AF: 0.466

GnomAD2 exomes AF: 0.484 AC: 74052 AN: 153104 AF XY: 0.500

Gnomad AFR exome AF: 0.375

Gnomad AMR exome AF: 0.387

Gnomad ASJ exome AF: 0.655

Gnomad EAS exome AF: 0.388

Gnomad FIN exome AF: 0.456

Gnomad NFE exome AF: 0.497

Gnomad OTH exome AF: 0.503

GnomAD4 exome AF: 0.484 AC: 670917 AN: 1386166 Hom.: 165095 Cov.: 26 AF XY: 0.490 AC XY: 335290 AN XY: 684556

African (AFR) AF: 0.384 AC: 12077 AN: 31418

American (AMR) AF: 0.395 AC: 14027 AN: 35530

Ashkenazi Jewish (ASJ) AF: 0.651 AC: 16315 AN: 25058

East Asian (EAS) AF: 0.425 AC: 15224 AN: 35846

South Asian (SAS) AF: 0.589 AC: 46527 AN: 79034

European-Finnish (FIN) AF: 0.450 AC: 21718 AN: 48260

Middle Eastern (MID) AF: 0.566 AC: 3203 AN: 5664

European-Non Finnish (NFE) AF: 0.482 AC: 514174 AN: 1067824

Other (OTH) AF: 0.481 AC: 27652 AN: 57532

GnomAD4 genome AF: 0.460 AC: 69738 AN: 151734 Hom.: 16438 Cov.: 30 AF XY: 0.462 AC XY: 34252 AN XY: 74146

African (AFR) AF: 0.378 AC: 15625 AN: 41358

American (AMR) AF: 0.443 AC: 6757 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.654 AC: 2268 AN: 3468

East Asian (EAS) AF: 0.404 AC: 2083 AN: 5150

South Asian (SAS) AF: 0.588 AC: 2828 AN: 4806

European-Finnish (FIN) AF: 0.458 AC: 4806 AN: 10502

Middle Eastern (MID) AF: 0.551 AC: 161 AN: 292

European-Non Finnish (NFE) AF: 0.496 AC: 33704 AN: 67894

Other (OTH) AF: 0.465 AC: 982 AN: 2110

Alfa AF: 0.493 Hom.: 73467

Bravo AF: 0.452

Asia WGS AF: 0.459 AC: 1603 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Apr 29, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 31838262) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.014
DANN	Benign	0.64
PhyloP100		-2.1
BranchPoint Hunter		0.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2071277; hg19: chr6-32171683; COSMIC: COSV66678352;