9-136334650-A-T

Variant names:

• chr9-136334650-A-T
• NM_001145638.3:c.272A>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001145638.3(GPSM1):​c.272A>T​(p.His91Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: GPSM1 NM_001145638.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.00

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.804

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPSM1	NM_001145638.3	c.272A>T	p.His91Leu	missense_variant	Exon 2 of 14	ENST00000440944.6	NP_001139110.2
GPSM1	NM_015597.6	c.272A>T	p.His91Leu	missense_variant	Exon 2 of 9		NP_056412.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPSM1	ENST00000440944.6	c.272A>T	p.His91Leu	missense_variant	Exon 2 of 14	5	NM_001145638.3	ENSP00000392828.1
GPSM1	ENST00000616132.4	c.272A>T	p.His91Leu	missense_variant	Exon 2 of 9	1		ENSP00000479405.1
GPSM1	ENST00000354753.7	c.368A>T	p.His123Leu	missense_variant	Exon 2 of 14	5		ENSP00000346797.4

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.272A>T (p.H91L) alteration is located in exon 2 (coding exon 2) of the GPSM1 gene. This alteration results from a A to T substitution at nucleotide position 272, causing the histidine (H) at amino acid position 91 to be replaced by a leucine (L). 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	0.27
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Benign	23
DANN	Benign	0.97
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.80	D;D;D
MetaSVM	Uncertain	-0.14	T
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-8.3	.;D;.
REVEL	Uncertain	0.62
Sift	Benign	0.10	.;T;.
Sift4G	Benign	0.079	T;T;.
Vest4		0.85
MutPred		0.49		Loss of disorder (P = 0.0452);Loss of disorder (P = 0.0452);.;
MVP		0.91
MPC		0.44
ClinPred		0.99	D
GERP RS		4.4
gMVP		0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr9-139229107;