rs1256262167

Variant names:

• chr12-125785-C-T
• rs1256262167
• NM_001170738.2:c.776C>T

Your query was ambiguous. Multiple possible variants found:

• chr12-125785-C-T
• chr12-125785-C-A

Variant summary

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

The NM_001170738.2(IQSEC3):​c.776C>T​(p.Ser259Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000461 in 1,517,550 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 (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000044 (0 hom.)
• Consequence: IQSEC3 NM_001170738.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.67
• Publications: 2 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=0.29234764).

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.776C>T	p.Ser259Phe	missense	Exon 3 of 14	NP_001164209.1	Q9UPP2-1
	IQSEC3	NM_015232.2		c.-6-12482C>T		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.776C>T	p.Ser259Phe	missense	Exon 3 of 14	ENSP00000437554.1	Q9UPP2-1
	IQSEC3	ENST00000382841.2	TSL:2	c.-6-12482C>T		intron	N/A	ENSP00000372292.2	Q9UPP2-2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152222 Hom.: 0 Cov.: 33

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000869 AC: 1 AN: 115054 AF XY: 0.00

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: 0.0000228

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000439 AC: 6 AN: 1365328 Hom.: 0 Cov.: 30 AF XY: 0.00000297 AC XY: 2 AN XY: 672770

African (AFR) AF: 0.00 AC: 0 AN: 30378

American (AMR) AF: 0.00 AC: 0 AN: 33112

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23724

East Asian (EAS) AF: 0.00 AC: 0 AN: 35230

South Asian (SAS) AF: 0.00 AC: 0 AN: 76742

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33096

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4682

European-Non Finnish (NFE) AF: 0.00000560 AC: 6 AN: 1071410

Other (OTH) AF: 0.00 AC: 0 AN: 56954

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152222 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74356

African (AFR) AF: 0.00 AC: 0 AN: 41448

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

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	0.093
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.026	T
Eigen	Benign	0.13
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.60	T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.69	N
PhyloP100		1.7
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.13
Sift	Uncertain	0.0030	D
Sift4G	Benign	0.24	T
Vest4		0.27
MutPred		0.25		Loss of phosphorylation at S259 (P = 0.0054)
MVP		0.31
MPC		0.43
ClinPred		0.41	T
GERP RS		5.5
Varity_R		0.12
gMVP		0.26
Mutation Taster		=79/21	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: rs1256262167; hg19: chr12-234951;