6-32219945-C-T

Variant names:

• chr6-32219945-C-T
• rs431722
• NM_004557.4:c.1316-159G>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.1316-159G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.585 in 151,884 control chromosomes in the GnomAD database, including 26,139 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.59 (26139 hom., cov: 32)
• Consequence: NOTCH4 NM_004557.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.60
• Publications: 16 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=-0.98).
• BP6: Variant 6-32219945-C-T is Benign according to our data. Variant chr6-32219945-C-T is described in ClinVar as Benign. ClinVar VariationId is 1279897.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.604 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOTCH4	NM_004557.4	c.1316-159G>A		intron_variant	Intron 7 of 29	ENST00000375023.3	NP_004548.3
NOTCH4	NR_134949.2	n.1455-159G>A		intron_variant	Intron 7 of 29
NOTCH4	NR_134950.2	n.1455-159G>A		intron_variant	Intron 7 of 28

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOTCH4	ENST00000375023.3	c.1316-159G>A		intron_variant	Intron 7 of 29	1	NM_004557.4	ENSP00000364163.3
NOTCH4	ENST00000473562.1	n.1445-159G>A		intron_variant	Intron 7 of 10	1

Frequencies

GnomAD3 genomes AF: 0.585 AC: 88839 AN: 151766 Hom.: 26137 Cov.: 32

Gnomad AFR AF: 0.563

Gnomad AMI AF: 0.590

Gnomad AMR AF: 0.558

Gnomad ASJ AF: 0.783

Gnomad EAS AF: 0.621

Gnomad SAS AF: 0.623

Gnomad FIN AF: 0.509

Gnomad MID AF: 0.637

Gnomad NFE AF: 0.601

Gnomad OTH AF: 0.599

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

GnomAD4 genome AF: 0.585 AC: 88886 AN: 151884 Hom.: 26139 Cov.: 32 AF XY: 0.580 AC XY: 43031 AN XY: 74210

African (AFR) AF: 0.563 AC: 23277 AN: 41374

American (AMR) AF: 0.558 AC: 8523 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.783 AC: 2716 AN: 3468

East Asian (EAS) AF: 0.622 AC: 3207 AN: 5160

South Asian (SAS) AF: 0.623 AC: 2993 AN: 4808

European-Finnish (FIN) AF: 0.509 AC: 5367 AN: 10542

Middle Eastern (MID) AF: 0.651 AC: 190 AN: 292

European-Non Finnish (NFE) AF: 0.601 AC: 40805 AN: 67944

Other (OTH) AF: 0.602 AC: 1270 AN: 2110

Alfa AF: 0.586 Hom.: 5703

Bravo AF: 0.592

Asia WGS AF: 0.599 AC: 2086 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	-0.98
CADD	Benign	0.10
DANN	Benign	0.56
PhyloP100		-2.6
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: rs431722; hg19: chr6-32187722; COSMIC: COSV107495998;