9-136337933-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001145638.3(GPSM1):c.790C>T(p.Arg264Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000552 in 1,611,512 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R264H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000051 (0 hom.)
• Consequence: GPSM1 NM_001145638.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.63

Genes affected

GPSM1 (HGNC:17858): (G protein signaling modulator 1) G-protein signaling modulators (GPSMs) play diverse functional roles through their interaction with G-protein subunits. This gene encodes a receptor-independent activator of G protein signaling, which is one of several factors that influence the basal activity of G-protein signaling systems. The protein contains seven tetratricopeptide repeats in its N-terminal half and four G-protein regulatory (GPR) motifs in its C-terminal half. Multiple alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1540243).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GPSM1	NM_001145638.3	c.790C>T	p.Arg264Cys	missense_variant	6/14	ENST00000440944.6
GPSM1	NM_015597.6	c.790C>T	p.Arg264Cys	missense_variant	6/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GPSM1	ENST00000440944.6	c.790C>T	p.Arg264Cys	missense_variant	6/14	5	NM_001145638.3	P1
GPSM1	ENST00000616132.4	c.790C>T	p.Arg264Cys	missense_variant	6/9	1
GPSM1	ENST00000354753.7	c.886C>T	p.Arg296Cys	missense_variant	6/14	5

Frequencies

GnomAD3 genomes AF: 0.0000985 AC: 15 AN: 152230 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000149 AC: 37 AN: 248410 Hom.: 0 AF XY: 0.0000815 AC XY: 11 AN XY: 134904

Gnomad AFR exome AF: 0.000188

Gnomad AMR exome AF: 0.000931

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000895

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.0000507 AC: 74 AN: 1459282 Hom.: 0 Cov.: 31 AF XY: 0.0000372 AC XY: 27 AN XY: 726002

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000784

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000243

Gnomad4 OTH exome AF: 0.0000663

GnomAD4 genome AF: 0.0000985 AC: 15 AN: 152230 Hom.: 0 Cov.: 34 AF XY: 0.000121 AC XY: 9 AN XY: 74360

Gnomad4 AFR AF: 0.0000965

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000128 Hom.: 0

Bravo AF: 0.000128

ExAC AF: 0.0000911 AC: 11

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 12, 2021

The c.790C>T (p.R264C) alteration is located in exon 6 (coding exon 6) of the GPSM1 gene. This alteration results from a C to T substitution at nucleotide position 790, causing the arginine (R) at amino acid position 264 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.11
Cadd	Uncertain	23
Dann	Uncertain	0.99
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.48	N
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.15	T;T;T
MetaSVM	Uncertain	0.080	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.55	T
Sift4G	Uncertain	0.0070	D;D;.
Vest4		0.45
MVP		0.79
MPC		0.21
ClinPred		0.070	T
GERP RS		0.99
gMVP		0.60

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

Publications

LitVar

Other links and lift over

dbSNP: rs782301159; hg19: chr9-139232390; COSMIC: COSV61303971;