22-40404540-C-T

Variant names:

• chr22-40404540-C-T
• rs2235318
• NM_015705.6:c.367-17C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_015705.6(SGSM3):​c.367-17C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.188 in 1,610,760 control chromosomes in the GnomAD database, including 33,154 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.19 (3236 hom., cov: 33)
  • Exomes 𝑓: 0.19 (29918 hom.)
• Consequence: SGSM3 NM_015705.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.93
• Publications: 8 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.359 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SGSM3	NM_015705.6	MANE Select	c.367-17C>T		intron	N/A	NP_056520.2
	SGSM3	NM_001350039.2		c.367-17C>T		intron	N/A	NP_001336968.1
	SGSM3	NM_001350040.2		c.367-17C>T		intron	N/A	NP_001336969.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SGSM3	ENST00000248929.14	TSL:1 MANE Select	c.367-17C>T		intron	N/A	ENSP00000248929.8	Q96HU1-1
	ENSG00000284431	ENST00000639722.1	TSL:5	n.*1605-17C>T		intron	N/A	ENSP00000492828.1	A0A1W2PRX2
	SGSM3	ENST00000956266.1		c.367-17C>T		intron	N/A	ENSP00000626325.1

Frequencies

GnomAD3 genomes AF: 0.187 AC: 28439 AN: 152006 Hom.: 3226 Cov.: 33

Gnomad AFR AF: 0.132

Gnomad AMI AF: 0.255

Gnomad AMR AF: 0.366

Gnomad ASJ AF: 0.102

Gnomad EAS AF: 0.212

Gnomad SAS AF: 0.138

Gnomad FIN AF: 0.227

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.180

Gnomad OTH AF: 0.171

GnomAD2 exomes AF: 0.225 AC: 56006 AN: 248436 AF XY: 0.211

Gnomad AFR exome AF: 0.126

Gnomad AMR exome AF: 0.552

Gnomad ASJ exome AF: 0.0956

Gnomad EAS exome AF: 0.182

Gnomad FIN exome AF: 0.220

Gnomad NFE exome AF: 0.185

Gnomad OTH exome AF: 0.199

GnomAD4 exome AF: 0.188 AC: 274108 AN: 1458636 Hom.: 29918 Cov.: 31 AF XY: 0.185 AC XY: 134494 AN XY: 725644

African (AFR) AF: 0.122 AC: 4060 AN: 33392

American (AMR) AF: 0.530 AC: 23573 AN: 44492

Ashkenazi Jewish (ASJ) AF: 0.0992 AC: 2591 AN: 26110

East Asian (EAS) AF: 0.261 AC: 10357 AN: 39612

South Asian (SAS) AF: 0.137 AC: 11793 AN: 86068

European-Finnish (FIN) AF: 0.223 AC: 11867 AN: 53258

Middle Eastern (MID) AF: 0.116 AC: 667 AN: 5768

European-Non Finnish (NFE) AF: 0.179 AC: 198905 AN: 1109668

Other (OTH) AF: 0.171 AC: 10295 AN: 60268

GnomAD4 genome AF: 0.187 AC: 28478 AN: 152124 Hom.: 3236 Cov.: 33 AF XY: 0.193 AC XY: 14324 AN XY: 74372

African (AFR) AF: 0.132 AC: 5481 AN: 41512

American (AMR) AF: 0.367 AC: 5602 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.102 AC: 353 AN: 3470

East Asian (EAS) AF: 0.212 AC: 1094 AN: 5156

South Asian (SAS) AF: 0.138 AC: 668 AN: 4828

European-Finnish (FIN) AF: 0.227 AC: 2408 AN: 10586

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.180 AC: 12248 AN: 67978

Other (OTH) AF: 0.170 AC: 357 AN: 2106

Alfa AF: 0.119 Hom.: 319

Bravo AF: 0.200

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.071
DANN	Benign	0.41
PhyloP100		-1.9
Mutation Taster		=100/0	polymorphism (auto)

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: rs2235318; hg19: chr22-40800544; COSMIC: COSV50651651; COSMIC: COSV50651651;