6-32222843-T-C

Variant names:

• chr6-32222843-T-C
• rs3134931
• NM_004557.4:c.156-37A>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.156-37A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.33 in 1,602,990 control chromosomes in the GnomAD database, including 91,817 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.37 (10893 hom., cov: 30)
  • Exomes 𝑓: 0.33 (80924 hom.)
• Consequence: NOTCH4 NM_004557.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.29
• Publications: 45 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=-0.9).
• BP6: Variant 6-32222843-T-C is Benign according to our data. Variant chr6-32222843-T-C is described in ClinVar as [Benign]. Clinvar id is 1294875.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.556 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOTCH4	NM_004557.4	c.156-37A>G		intron_variant	Intron 2 of 29	ENST00000375023.3	NP_004548.3
NOTCH4	NR_134949.2	n.295-37A>G		intron_variant	Intron 2 of 29
NOTCH4	NR_134950.2	n.295-37A>G		intron_variant	Intron 2 of 28

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOTCH4	ENST00000375023.3	c.156-37A>G		intron_variant	Intron 2 of 29	1	NM_004557.4	ENSP00000364163.3
NOTCH4	ENST00000473562.1	n.285-37A>G		intron_variant	Intron 2 of 10	1

Frequencies

GnomAD3 genomes AF: 0.368 AC: 55791 AN: 151702 Hom.: 10883 Cov.: 30

Gnomad AFR AF: 0.474

Gnomad AMI AF: 0.281

Gnomad AMR AF: 0.354

Gnomad ASJ AF: 0.420

Gnomad EAS AF: 0.574

Gnomad SAS AF: 0.480

Gnomad FIN AF: 0.221

Gnomad MID AF: 0.339

Gnomad NFE AF: 0.303

Gnomad OTH AF: 0.397

GnomAD2 exomes AF: 0.352 AC: 85394 AN: 242654 AF XY: 0.355

Gnomad AFR exome AF: 0.477

Gnomad AMR exome AF: 0.322

Gnomad ASJ exome AF: 0.418

Gnomad EAS exome AF: 0.550

Gnomad FIN exome AF: 0.221

Gnomad NFE exome AF: 0.298

Gnomad OTH exome AF: 0.350

GnomAD4 exome AF: 0.326 AC: 472774 AN: 1451170 Hom.: 80924 Cov.: 32 AF XY: 0.330 AC XY: 238339 AN XY: 722138

African (AFR) AF: 0.476 AC: 15588 AN: 32762

American (AMR) AF: 0.329 AC: 13814 AN: 42040

Ashkenazi Jewish (ASJ) AF: 0.413 AC: 10625 AN: 25740

East Asian (EAS) AF: 0.558 AC: 22135 AN: 39638

South Asian (SAS) AF: 0.467 AC: 39903 AN: 85492

European-Finnish (FIN) AF: 0.223 AC: 11907 AN: 53344

Middle Eastern (MID) AF: 0.367 AC: 2083 AN: 5678

European-Non Finnish (NFE) AF: 0.304 AC: 336165 AN: 1106612

Other (OTH) AF: 0.343 AC: 20554 AN: 59864

GnomAD4 genome AF: 0.368 AC: 55849 AN: 151820 Hom.: 10893 Cov.: 30 AF XY: 0.367 AC XY: 27213 AN XY: 74208

African (AFR) AF: 0.474 AC: 19617 AN: 41352

American (AMR) AF: 0.355 AC: 5412 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.420 AC: 1452 AN: 3458

East Asian (EAS) AF: 0.573 AC: 2955 AN: 5156

South Asian (SAS) AF: 0.480 AC: 2315 AN: 4822

European-Finnish (FIN) AF: 0.221 AC: 2334 AN: 10582

Middle Eastern (MID) AF: 0.344 AC: 101 AN: 294

European-Non Finnish (NFE) AF: 0.303 AC: 20580 AN: 67890

Other (OTH) AF: 0.393 AC: 827 AN: 2104

Alfa AF: 0.319 Hom.: 25032

Bravo AF: 0.383

Asia WGS AF: 0.439 AC: 1525 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	-0.90
CADD	Benign	0.79
DANN	Benign	0.51
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: rs3134931; hg19: chr6-32190620; COSMIC: COSV100900529;