22-40404360-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_015705.6(SGSM3):c.271G>A(p.Asp91Asn) 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 benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SGSM3 NM_015705.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.49

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.41897705).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SGSM3	NM_015705.6	c.271G>A	p.Asp91Asn	missense_variant	5/22	ENST00000248929.14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SGSM3	ENST00000248929.14	c.271G>A	p.Asp91Asn	missense_variant	5/22	1	NM_015705.6	P1
SGSM3	ENST00000457767.5	c.70G>A	p.Asp24Asn	missense_variant	4/8	2
SGSM3	ENST00000478085.5	n.248G>A		non_coding_transcript_exon_variant	1/9	2
SGSM3	ENST00000485962.5	n.432G>A		non_coding_transcript_exon_variant	5/20	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1454324 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 722876

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: 0.00

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

Mar 24, 2023

The c.271G>A (p.D91N) alteration is located in exon 5 (coding exon 4) of the SGSM3 gene. This alteration results from a G to A substitution at nucleotide position 271, causing the aspartic acid (D) at amino acid position 91 to be replaced by an asparagine (N). 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	0.70
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.084	T;T
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.42	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-2.8	D;D
REVEL	Benign	0.17
Sift	Benign	0.13	T;D
Sift4G	Benign	0.063	T;D
Polyphen		0.57	.;P
Vest4		0.90
MutPred		0.36		.;Gain of MoRF binding (P = 0.1054);
MVP		0.48
MPC		0.58
ClinPred		0.94	D
GERP RS		5.6
Varity_R		0.28
gMVP		0.56

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: chr22-40800364;