9-136327712-C-A

Variant names:

• chr9-136327712-C-A
• rs1300949168
• NM_001145638.3:c.17C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001145638.3(GPSM1):​c.17C>A​(p.Pro6Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000983 in 1,017,672 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P6L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 9.8e-7 (0 hom.)
• Consequence: GPSM1 NM_001145638.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.122
• Publications: 0 publications found

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]

DKFZP434A062 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28860384).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001145638.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPSM1	NM_001145638.3	MANE Select	c.17C>A	p.Pro6Gln	missense	Exon 1 of 14	NP_001139110.2	A0A0A0MSK4
	GPSM1	NM_015597.6		c.17C>A	p.Pro6Gln	missense	Exon 1 of 9	NP_056412.5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPSM1	ENST00000440944.6	TSL:5 MANE Select	c.17C>A	p.Pro6Gln	missense	Exon 1 of 14	ENSP00000392828.1	A0A0A0MSK4
	GPSM1	ENST00000616132.4	TSL:1	c.17C>A	p.Pro6Gln	missense	Exon 1 of 9	ENSP00000479405.1	A0A087WVF5
	DKFZP434A062	ENST00000848857.1		n.-70G>T		upstream_gene	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 9.83e-7 AC: 1 AN: 1017672 Hom.: 0 Cov.: 21 AF XY: 0.00 AC XY: 0 AN XY: 484642

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 20190

American (AMR) AF: 0.00 AC: 0 AN: 6680

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11448

East Asian (EAS) AF: 0.00 AC: 0 AN: 19420

South Asian (SAS) AF: 0.00 AC: 0 AN: 20088

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 17202

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2620

European-Non Finnish (NFE) AF: 0.00000113 AC: 1 AN: 881362

Other (OTH) AF: 0.00 AC: 0 AN: 38662

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.054	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	21
DANN	Benign	0.97
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.51	T
M_CAP	Pathogenic	0.97	D
MetaRNN	Benign	0.29	T
MetaSVM	Uncertain	0.13	D
PhyloP100		0.12
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.38	N
REVEL	Uncertain	0.31
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	D
Vest4		0.17
MutPred		0.20		Loss of glycosylation at P6 (P = 0.0771)
MVP		0.97
MPC		0.14
ClinPred		0.38	T
GERP RS		1.9
PromoterAI		0.11	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.19
Mutation Taster		=96/4	polymorphism

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: rs1300949168; hg19: chr9-139222168;