Genetic Variant SGSM3:p.Lys161Gln (chr22-40405147-A-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

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

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.10

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.765

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.481A>C	p.Lys161Gln	missense	Exon 7 of 22	NP_056520.2
SGSM3	NM_001350039.2		c.481A>C	p.Lys161Gln	missense	Exon 7 of 22	NP_001336968.1
SGSM3	NM_001350040.2		c.481A>C	p.Lys161Gln	missense	Exon 7 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.481A>C	p.Lys161Gln	missense	Exon 7 of 22	ENSP00000248929.8	Q96HU1-1
ENSG00000284431	ENST00000639722.1	TSL:5	n.*1719A>C		non_coding_transcript_exon	Exon 18 of 31	ENSP00000492828.1	A0A1W2PRX2
ENSG00000284431	ENST00000639722.1	TSL:5	n.*1719A>C		3_prime_UTR	Exon 18 of 31	ENSP00000492828.1	A0A1W2PRX2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000659

AC:

AN:

1366356

Hom.:

Cov.:

AF XY:

0.00000744

AC XY:

AN XY:

671844

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29940

American (AMR)

AF:

0.00

AC:

AN:

29810

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21322

East Asian (EAS)

AF:

0.00

AC:

AN:

36414

South Asian (SAS)

AF:

0.00

AC:

AN:

73494

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50428

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5400

European-Non Finnish (NFE)

AF:

0.00000846

AC:

AN:

1063672

Other (OTH)

AF:

0.00

AC:

AN:

55876

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

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

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.060

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.096

Eigen

Pathogenic

0.69

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.053

MetaRNN

Pathogenic

0.76

MetaSVM

Benign

-1.0

MutationAssessor

Pathogenic

3.0

PhyloP100

7.1

PrimateAI

Uncertain

0.58

PROVEAN

Uncertain

-3.2

REVEL

Uncertain

0.46

Sift

Benign

0.17

Sift4G

Benign

0.14

Polyphen

0.99

Vest4

0.91

MutPred

0.65

Loss of ubiquitination at K161 (P = 0.0161)

MVP

0.48

MPC

0.68

ClinPred

0.97

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.68

gMVP

0.68

Mutation Taster

=69/31

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over