chr22-40404396-C-T

Variant names:

• chr22-40404396-C-T
• rs143730708
• NM_015705.6:c.307C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_001350048.2(SGSM3):​c.-239C>T variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.000407 in 1,608,836 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00066 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00038 (1 hom.)
• Consequence: SGSM3 NM_001350048.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.63
• Publications: 2 publications found

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

ENSG00000284431 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009180725).
• BP6: Variant 22-40404396-C-T is Benign according to our data. Variant chr22-40404396-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 742761.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001350048.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SGSM3	NM_015705.6	MANE Select	c.307C>T	p.Arg103Cys	missense	Exon 5 of 22	NP_056520.2
	SGSM3	NM_001350048.2		c.-239C>T		5_prime_UTR_premature_start_codon_gain	Exon 4 of 21	NP_001336977.1
	SGSM3	NM_001350039.2		c.307C>T	p.Arg103Cys	missense	Exon 5 of 22	NP_001336968.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SGSM3	ENST00000248929.14	TSL:1 MANE Select	c.307C>T	p.Arg103Cys	missense	Exon 5 of 22	ENSP00000248929.8	Q96HU1-1
	ENSG00000284431	ENST00000639722.1	TSL:5	n.*1545C>T		non_coding_transcript_exon	Exon 16 of 31	ENSP00000492828.1	A0A1W2PRX2
	ENSG00000284431	ENST00000639722.1	TSL:5	n.*1545C>T		3_prime_UTR	Exon 16 of 31	ENSP00000492828.1	A0A1W2PRX2

Frequencies

GnomAD3 genomes AF: 0.000664 AC: 101 AN: 152182 Hom.: 1 Cov.: 33

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: 0.00744

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000890 AC: 219 AN: 246000 AF XY: 0.000941

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.0000294

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00775

Gnomad NFE exome AF: 0.000252

Gnomad OTH exome AF: 0.00118

GnomAD4 exome AF: 0.000380 AC: 554 AN: 1456536 Hom.: 1 Cov.: 31 AF XY: 0.000373 AC XY: 270 AN XY: 724192

African (AFR) AF: 0.000329 AC: 11 AN: 33398

American (AMR) AF: 0.0000226 AC: 1 AN: 44208

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25668

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39664

South Asian (SAS) AF: 0.000304 AC: 26 AN: 85494

European-Finnish (FIN) AF: 0.00648 AC: 344 AN: 53056

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 0.000127 AC: 141 AN: 1109154

Other (OTH) AF: 0.000416 AC: 25 AN: 60152

GnomAD4 genome AF: 0.000663 AC: 101 AN: 152300 Hom.: 1 Cov.: 33 AF XY: 0.000913 AC XY: 68 AN XY: 74452

African (AFR) AF: 0.0000481 AC: 2 AN: 41556

American (AMR) AF: 0.00 AC: 0 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00744 AC: 79 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000165 Hom.: 0

Bravo AF: 0.000140

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000675 AC: 82

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.38
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.10	T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.0092	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		4.6
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Benign	0.13
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.30	B
Vest4		0.30
MVP		0.36
MPC		0.21
ClinPred		0.080	T
GERP RS		4.8
Varity_R		0.44
gMVP		0.54
Mutation Taster		=83/17	polymorphism

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

Other links and lift over

dbSNP: rs143730708; hg19: chr22-40800400;