Variant 22-24855679-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001098497.3(SGSM1):c.800C>T(p.Pro267Leu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000128 in 1,613,942 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00013 ( 1 hom. )

Consequence

SGSM1
NM_001098497.3 missense, splice_region

Scores

Splicing: ADA: 0.8227

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.04

Variant links:

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]

SGSM1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.857

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SGSM1	NM_001098497.3 link	c.800C>T	p.Pro267Leu	missense_variant, splice_region_variant	8/25	ENST00000400358.9	NP_001091967.1	Q2NKQ1-4
SGSM1	NM_001039948.4 link	c.800C>T	p.Pro267Leu	missense_variant, splice_region_variant	8/26		NP_001035037.1	Q2NKQ1-1
SGSM1	NM_133454.4 link	c.800C>T	p.Pro267Leu	missense_variant, splice_region_variant	8/25		NP_597711.1	Q2NKQ1A0A087X241
SGSM1	NM_001098498.3 link	c.800C>T	p.Pro267Leu	missense_variant, splice_region_variant	8/24		NP_001091968.1	Q2NKQ1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SGSM1	ENST00000400358.9 link	c.800C>T	p.Pro267Leu	missense_variant, splice_region_variant	8/25	1	NM_001098497.3	ENSP00000383211.4		Q2NKQ1-4

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000104

AC:

AN:

248928

Hom.:

AF XY:

0.000104

AC XY:

AN XY:

135036

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000111

Gnomad SAS exome

AF:

0.000229

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000106

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.000133

AC:

195

AN:

1461700

Hom.:

Cov.:

AF XY:

0.000116

AC XY:

AN XY:

727130

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000134

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.000139

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000146

Gnomad4 OTH exome

AF:

0.000199

GnomAD4 genome

AF:

0.0000723

AC:

AN:

152242

Hom.:

Cov.:

AF XY:

0.0000941

AC XY:

AN XY:

74412

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000387

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000893

Hom.:

Bravo

AF:

0.0000680

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000120

AC:

ExAC

AF:

0.0000413

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 10, 2024

The c.800C>T (p.P267L) alteration is located in exon 8 (coding exon 8) of the SGSM1 gene. This alteration results from a C to T substitution at nucleotide position 800, causing the proline (P) at amino acid position 267 to be replaced by a leucine (L). 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

0.86

BayesDel_addAF

Benign

-0.0084

BayesDel_noAF

Uncertain

0.050

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

.;.;T

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D;D

M_CAP

Benign

0.047

MetaRNN

Pathogenic

0.86

D;D;D

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.2

.;M;M

PrimateAI

Pathogenic

0.89

PROVEAN

Pathogenic

-9.4

.;D;D

REVEL

Uncertain

0.45

Sift

Uncertain

0.0010

.;D;D

Sift4G

Uncertain

0.032

D;D;D

Polyphen

1.0, 1.0

.;D;D

Vest4

0.96

MVP

0.55

MPC

0.39

ClinPred

0.97

GERP RS

4.0

Varity_R

0.77

gMVP

0.67

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.82

dbscSNV1_RF

Benign

0.70

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over