22-40405147-A-C

Variant summary

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

The NM_015705.6(SGSM3):c.481A>C(p.Lys161Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000659 in 1,366,356 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000066 (0 hom.)
• Consequence: SGSM3 NM_015705.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.10

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.765

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SGSM3	NM_015705.6	c.481A>C	p.Lys161Gln	missense_variant	7/22	ENST00000248929.14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SGSM3	ENST00000248929.14	c.481A>C	p.Lys161Gln	missense_variant	7/22	1	NM_015705.6	P1
SGSM3	ENST00000457767.5	c.280A>C	p.Lys94Gln	missense_variant	6/8	2
SGSM3	ENST00000478085.5	n.458A>C		non_coding_transcript_exon_variant	3/9	2
SGSM3	ENST00000485962.5	n.642A>C		non_coding_transcript_exon_variant	7/20	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000659 AC: 9 AN: 1366356 Hom.: 0 Cov.: 31 AF XY: 0.00000744 AC XY: 5 AN XY: 671844

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000846

Gnomad4 OTH exome AF: 0.00

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

Jan 10, 2023

The c.481A>C (p.K161Q) alteration is located in exon 7 (coding exon 6) of the SGSM3 gene. This alteration results from a A to C substitution at nucleotide position 481, causing the lysine (K) at amino acid position 161 to be replaced by a glutamine (Q). 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	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
Cadd	Pathogenic	26
Dann	Uncertain	0.99
DEOGEN2	Benign	0.096	T;T
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Benign	0.053	D
MetaRNN	Pathogenic	0.76	D;D
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.2	D;D
REVEL	Uncertain	0.46
Sift	Benign	0.17	T;T
Sift4G	Benign	0.14	T;T
Polyphen		0.99	.;D
Vest4		0.91
MutPred		0.65		.;Loss of ubiquitination at K161 (P = 0.0161);
MVP		0.48
MPC		0.68
ClinPred		0.97	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.68
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: chr22-40801151;