Genetic Variant SGSM3:p.Ala63Glu (chr22-40404277-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_015705.6(SGSM3):c.188C>A(p.Ala63Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000592 in 1,520,822 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A63V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000044 ( 0 hom. )

Consequence

SGSM3
NM_015705.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.253

Publications

1 publications found

Variant links:

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]

SGSM3 Gene-Disease associations (from GenCC):

neurodevelopmental disorder
Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, PanelApp Australia
intellectual disability
Inheritance: AR Classification: LIMITED Submitted by: G2P

SGSM3 links:

ENSG00000284431 (HGNC:):

ENSG00000284431 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.035225928).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015705.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SGSM3	NM_015705.6	MANE Select	c.188C>A	p.Ala63Glu	missense	Exon 5 of 22	NP_056520.2
SGSM3	NM_001350039.2		c.188C>A	p.Ala63Glu	missense	Exon 5 of 22	NP_001336968.1
SGSM3	NM_001350040.2		c.188C>A	p.Ala63Glu	missense	Exon 5 of 22	NP_001336969.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SGSM3	ENST00000248929.14	TSL:1 MANE Select	c.188C>A	p.Ala63Glu	missense	Exon 5 of 22	ENSP00000248929.8	Q96HU1-1
ENSG00000284431	ENST00000639722.1	TSL:5	n.*1426C>A		non_coding_transcript_exon	Exon 16 of 31	ENSP00000492828.1	A0A1W2PRX2
ENSG00000284431	ENST00000639722.1	TSL:5	n.*1426C>A		3_prime_UTR	Exon 16 of 31	ENSP00000492828.1	A0A1W2PRX2

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000551

AC:

AN:

181382

AF XY:

0.0000105

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000114

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000438

AC:

AN:

1368630

Hom.:

Cov.:

AF XY:

0.00000597

AC XY:

AN XY:

670342

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30472

American (AMR)

AF:

0.00

AC:

AN:

30688

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20192

East Asian (EAS)

AF:

0.00

AC:

AN:

38710

South Asian (SAS)

AF:

0.00

AC:

AN:

71026

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49960

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5334

European-Non Finnish (NFE)

AF:

0.00000563

AC:

AN:

1065958

Other (OTH)

AF:

0.00

AC:

AN:

56290

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74338

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41444

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

ExAC

AF:

0.00000828

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.75

CADD

Benign

0.063

(source)

DANN

Benign

0.21

DEOGEN2

Benign

0.048

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.36

M_CAP

Benign

0.0058

MetaRNN

Benign

0.035

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-0.20

PhyloP100

-0.25

PrimateAI

Benign

0.30

PROVEAN

Benign

-1.1

REVEL

Benign

0.085

Sift

Benign

0.92

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.077

MutPred

0.29

Gain of disorder (P = 0.0547)

MVP

0.088

MPC

0.18

ClinPred

0.012

GERP RS

-2.6

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.1

Varity_R

0.049

gMVP

0.29

Mutation Taster

=97/3

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over