22-24855315-T-A

Position:

• chr22-24855315-T-A

Variant summary

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

The NM_001098497.3(SGSM1):​c.554T>A​(p.Met185Lys) 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: 31)
• Consequence: SGSM1 NM_001098497.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.10

Genes affected

SGSM1 (HGNC:29410): (small G protein signaling modulator 1) Enables GTPase activator activity and small GTPase binding activity. Predicted to be involved in activation of GTPase activity and intracellular protein transport. Predicted to act upstream of or within positive regulation of transcription by RNA polymerase II. Located in cytoplasmic vesicle membrane and 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
SGSM1	NM_001098497.3	c.554T>A	p.Met185Lys	missense_variant	7/25	ENST00000400358.9	NP_001091967.1
SGSM1	NM_001039948.4	c.554T>A	p.Met185Lys	missense_variant	7/26		NP_001035037.1
SGSM1	NM_133454.4	c.554T>A	p.Met185Lys	missense_variant	7/25		NP_597711.1
SGSM1	NM_001098498.3	c.554T>A	p.Met185Lys	missense_variant	7/24		NP_001091968.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SGSM1	ENST00000400358.9	c.554T>A	p.Met185Lys	missense_variant	7/25	1	NM_001098497.3	ENSP00000383211.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

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.554T>A (p.M185K) alteration is located in exon 7 (coding exon 7) of the SGSM1 gene. This alteration results from a T to A substitution at nucleotide position 554, causing the methionine (M) at amino acid position 185 to be replaced by a lysine (K). 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	0.85
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	.;.;T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Benign	0.038	D
MetaRNN	Uncertain	0.73	D;D;D
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	2.0	.;M;M
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-4.1	.;D;D
REVEL	Uncertain	0.44
Sift	Uncertain	0.0080	.;D;D
Sift4G	Uncertain	0.0080	D;D;D
Polyphen		0.98, 0.99	.;D;D
Vest4		0.74
MutPred		0.70		Gain of methylation at K186 (P = 0.0203);Gain of methylation at K186 (P = 0.0203);Gain of methylation at K186 (P = 0.0203);
MVP		0.32
MPC		1.0
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.80
gMVP		0.83

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

LitVar

Other links and lift over

dbSNP: rs1930704106; hg19: chr22-25251282;