rs8192583

Variant names:

• chr6-32195497-G-A
• rs8192583
• ENST00000375043.3:c.-347C>T

Your query was ambiguous. Multiple possible variants found:

• chr6-32195497-G-A
• chr6-32195497-G-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000375043.3(GPSM3):​c.-347C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0436 in 1,612,868 control chromosomes in the GnomAD database, including 1,758 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.042 (164 hom., cov: 32)
  • Exomes 𝑓: 0.044 (1594 hom.)
• Consequence: GPSM3 ENST00000375043.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.713
• Publications: 23 publications found

Genes affected

GPSM3 (HGNC:13945): (G protein signaling modulator 3) Predicted to enable GTPase regulator activity. Predicted to be involved in positive regulation of inflammatory response. Predicted to act upstream of or within positive regulation of cytokine production involved in inflammatory response and positive regulation of leukocyte chemotaxis. Predicted to be located in cytoplasm and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

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 6-32195497-G-A is Benign according to our data. Variant chr6-32195497-G-A is described in ClinVar as Benign. ClinVar VariationId is 1232666.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.053 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOTCH4	NM_004557.4	c.5952C>T	p.Asp1984Asp	synonymous_variant	Exon 30 of 30	ENST00000375023.3	NP_004548.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOTCH4	ENST00000375023.3	c.5952C>T	p.Asp1984Asp	synonymous_variant	Exon 30 of 30	1	NM_004557.4	ENSP00000364163.3

Frequencies

GnomAD3 genomes AF: 0.0423 AC: 6433 AN: 152208 Hom.: 166 Cov.: 32

Gnomad AFR AF: 0.0502

Gnomad AMI AF: 0.158

Gnomad AMR AF: 0.0233

Gnomad ASJ AF: 0.0127

Gnomad EAS AF: 0.00886

Gnomad SAS AF: 0.0592

Gnomad FIN AF: 0.0175

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0468

Gnomad OTH AF: 0.0430

GnomAD2 exomes AF: 0.0354 AC: 8705 AN: 245784 AF XY: 0.0374

Gnomad AFR exome AF: 0.0551

Gnomad AMR exome AF: 0.0166

Gnomad ASJ exome AF: 0.0120

Gnomad EAS exome AF: 0.00443

Gnomad FIN exome AF: 0.0181

Gnomad NFE exome AF: 0.0437

Gnomad OTH exome AF: 0.0337

GnomAD4 exome AF: 0.0437 AC: 63881 AN: 1460542 Hom.: 1594 Cov.: 31 AF XY: 0.0437 AC XY: 31747 AN XY: 726584

African (AFR) AF: 0.0569 AC: 1904 AN: 33480

American (AMR) AF: 0.0183 AC: 819 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.0131 AC: 341 AN: 26116

East Asian (EAS) AF: 0.00292 AC: 116 AN: 39692

South Asian (SAS) AF: 0.0535 AC: 4617 AN: 86238

European-Finnish (FIN) AF: 0.0202 AC: 1058 AN: 52304

Middle Eastern (MID) AF: 0.0331 AC: 191 AN: 5768

European-Non Finnish (NFE) AF: 0.0470 AC: 52274 AN: 1111854

Other (OTH) AF: 0.0424 AC: 2561 AN: 60384

GnomAD4 genome AF: 0.0422 AC: 6426 AN: 152326 Hom.: 164 Cov.: 32 AF XY: 0.0405 AC XY: 3020 AN XY: 74490

African (AFR) AF: 0.0501 AC: 2081 AN: 41566

American (AMR) AF: 0.0233 AC: 357 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0127 AC: 44 AN: 3470

East Asian (EAS) AF: 0.00888 AC: 46 AN: 5182

South Asian (SAS) AF: 0.0586 AC: 283 AN: 4830

European-Finnish (FIN) AF: 0.0175 AC: 186 AN: 10624

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0468 AC: 3182 AN: 68026

Other (OTH) AF: 0.0426 AC: 90 AN: 2114

Alfa AF: 0.0433 Hom.: 144

Bravo AF: 0.0431

Asia WGS AF: 0.0220 AC: 77 AN: 3478

EpiCase AF: 0.0492

EpiControl AF: 0.0458

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

May 05, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.24
DANN	Benign	0.80
PhyloP100		-0.71
PromoterAI		0.00010	Neutral
Mutation Taster		=299/1	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: rs8192583; hg19: chr6-32163274; COSMIC: COSV66678918;