NM_001170738.2:c.683C>A

Variant names:

• chr12-125692-C-A
• rs377259498
• NM_001170738.2:c.683C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001170738.2(IQSEC3):​c.683C>A​(p.Ala228Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A228V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: IQSEC3 NM_001170738.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.624
• Publications: 0 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1812998).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IQSEC3	NM_001170738.2	c.683C>A	p.Ala228Glu	missense_variant	Exon 3 of 14	ENST00000538872.6	NP_001164209.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IQSEC3	ENST00000538872.6	c.683C>A	p.Ala228Glu	missense_variant	Exon 3 of 14	5	NM_001170738.2	ENSP00000437554.1
IQSEC3	ENST00000382841.2	c.-6-12575C>A		intron_variant	Intron 2 of 12	2		ENSP00000372292.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1379612 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 681542

African (AFR) AF: 0.00 AC: 0 AN: 30000

American (AMR) AF: 0.00 AC: 0 AN: 35322

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22180

East Asian (EAS) AF: 0.00 AC: 0 AN: 37274

South Asian (SAS) AF: 0.00 AC: 0 AN: 74950

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5516

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1082368

Other (OTH) AF: 0.00 AC: 0 AN: 57390

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.019	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.45	T
M_CAP	Uncertain	0.27	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.62
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.52	N
REVEL	Benign	0.12
Sift	Uncertain	0.025	D
Sift4G	Benign	0.56	T
Vest4		0.25
MutPred		0.40		Gain of catalytic residue at V223 (P = 0.0044);
MVP		0.39
MPC		0.67
ClinPred		0.21	T
GERP RS		0.77
Varity_R		0.077
gMVP		0.32
Mutation Taster		=97/3	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: rs377259498; hg19: chr12-234858;