12-125767-C-G

Variant names:

• chr12-125767-C-G
• rs372928257
• NM_001170738.2:c.758C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001170738.2(IQSEC3):​c.758C>G​(p.Pro253Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000735 in 1,360,406 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P253L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: IQSEC3 NM_001170738.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.12
• Publications: 1 publications found

Genes affected

IQSEC3 (HGNC:29193): (IQ motif and Sec7 domain ArfGEF 3) Predicted to enable guanyl-nucleotide exchange factor activity. Predicted to be involved in several processes, including actin cytoskeleton organization; activation of GTPase activity; and regulation of small GTPase mediated signal transduction. Located in cytosol and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30314896).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001170738.2. 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
	IQSEC3	NM_001170738.2	MANE Select	c.758C>G	p.Pro253Arg	missense	Exon 3 of 14	NP_001164209.1	Q9UPP2-1
	IQSEC3	NM_015232.2		c.-6-12500C>G		intron	N/A	NP_056047.1	Q9UPP2-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IQSEC3	ENST00000538872.6	TSL:5 MANE Select	c.758C>G	p.Pro253Arg	missense	Exon 3 of 14	ENSP00000437554.1	Q9UPP2-1
	IQSEC3	ENST00000382841.2	TSL:2	c.-6-12500C>G		intron	N/A	ENSP00000372292.2	Q9UPP2-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.35e-7 AC: 1 AN: 1360406 Hom.: 0 Cov.: 30 AF XY: 0.00000149 AC XY: 1 AN XY: 669712

African (AFR) AF: 0.0000330 AC: 1 AN: 30262

American (AMR) AF: 0.00 AC: 0 AN: 32358

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23102

East Asian (EAS) AF: 0.00 AC: 0 AN: 35384

South Asian (SAS) AF: 0.00 AC: 0 AN: 75230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32948

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4910

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1069478

Other (OTH) AF: 0.00 AC: 0 AN: 56734

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.020	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.67	T
M_CAP	Pathogenic	0.32	D
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.90	L
PhyloP100		1.1
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.055
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.11	T
Vest4		0.34
MutPred		0.23		Gain of methylation at P253 (P = 0.0317)
MVP		0.25
MPC		0.92
ClinPred		0.57	D
GERP RS		1.1
Varity_R		0.026
gMVP		0.19
Mutation Taster		=93/7	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: rs372928257; hg19: chr12-234933;