9-136336991-A-G

Position:

• chr9-136336991-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001145638.3(GPSM1):​c.497A>G​(p.Asn166Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: GPSM1 NM_001145638.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.405

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05187127).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GPSM1	NM_001145638.3	c.497A>G	p.Asn166Ser	missense_variant	4/14	ENST00000440944.6	NP_001139110.2
GPSM1	NM_015597.6	c.497A>G	p.Asn166Ser	missense_variant	4/9		NP_056412.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GPSM1	ENST00000440944.6	c.497A>G	p.Asn166Ser	missense_variant	4/14	5	NM_001145638.3	ENSP00000392828	P1
GPSM1	ENST00000616132.4	c.497A>G	p.Asn166Ser	missense_variant	4/9	1		ENSP00000479405
GPSM1	ENST00000354753.7	c.593A>G	p.Asn198Ser	missense_variant	4/14	5		ENSP00000346797

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

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

Jun 22, 2024

The c.497A>G (p.N166S) alteration is located in exon 4 (coding exon 4) of the GPSM1 gene. This alteration results from a A to G substitution at nucleotide position 497, causing the asparagine (N) at amino acid position 166 to be replaced by a serine (S). 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	0.070
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	0.028
DANN	Benign	0.23
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.059	N
LIST_S2	Benign	0.73	T;T;T
M_CAP	Benign	0.058	D
MetaRNN	Benign	0.052	T;T;T
MetaSVM	Benign	-0.87	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.15	.;N;.
REVEL	Benign	0.14
Sift	Benign	1.0	.;T;.
Sift4G	Benign	0.65	T;T;.
Vest4		0.23
MutPred		0.27		Gain of disorder (P = 0.0774);Gain of disorder (P = 0.0774);.;
MVP		0.76
MPC		0.12
ClinPred		0.026	T
GERP RS		-2.5
gMVP		0.34

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-139231448; COSMIC: COSV100696678;