22-40404632-A-G

Position:

• chr22-40404632-A-G

Variant summary

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

The ENST00000248929.14(SGSM3):​c.442A>G​(p.Ser148Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SGSM3 ENST00000248929.14 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.09

Genes affected

SGSM3 (HGNC:25228): (small G protein signaling modulator 3) Enables GTPase activator activity and small GTPase binding activity. Involved in several processes, including Rap protein signal transduction; positive regulation of GTPase activity; and regulation of Rab protein signal transduction. Located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SGSM3	NM_015705.6	c.442A>G	p.Ser148Gly	missense_variant	6/22	ENST00000248929.14	NP_056520.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SGSM3	ENST00000248929.14	c.442A>G	p.Ser148Gly	missense_variant	6/22	1	NM_015705.6	ENSP00000248929	P1
SGSM3	ENST00000457767.5	c.241A>G	p.Ser81Gly	missense_variant	5/8	2		ENSP00000399249
SGSM3	ENST00000478085.5	n.419A>G		non_coding_transcript_exon_variant	2/9	2
SGSM3	ENST00000485962.5	n.603A>G		non_coding_transcript_exon_variant	6/20	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Feb 28, 2023

The c.442A>G (p.S148G) alteration is located in exon 6 (coding exon 5) of the SGSM3 gene. This alteration results from a A to G substitution at nucleotide position 442, causing the serine (S) at amino acid position 148 to be replaced by a glycine (G). 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	0.15
BayesDel_addAF	Uncertain	0.014	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.076	T;T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Benign	0.015	T
MetaRNN	Uncertain	0.47	T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.2	.;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.5	D;D
REVEL	Benign	0.20
Sift	Uncertain	0.014	D;T
Sift4G	Uncertain	0.030	D;D
Polyphen		0.24	.;B
Vest4		0.49
MutPred		0.47		.;Loss of phosphorylation at S148 (P = 0.0742);
MVP		0.30
MPC		0.47
ClinPred		0.94	D
GERP RS		5.9
Varity_R		0.67
gMVP		0.69

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: chr22-40800636;