12-99183-G-T

Variant names:

• chr12-99183-G-T
• rs782035854
• NM_001170738.2:c.592G>T

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.592G>T​(p.Ala198Ser) variant causes a missense change. 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. A198T) 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: 4.25
• 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=0.24687052).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IQSEC3	NM_001170738.2	c.592G>T	p.Ala198Ser	missense_variant	Exon 2 of 14	ENST00000538872.6	NP_001164209.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IQSEC3	ENST00000538872.6	c.592G>T	p.Ala198Ser	missense_variant	Exon 2 of 14	5	NM_001170738.2	ENSP00000437554.1
IQSEC3	ENST00000382841.2	c.-38G>T		5_prime_UTR_variant	Exon 2 of 13	2		ENSP00000372292.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1446590 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 719988

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 86144

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38788

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111676

Other (OTH) AF: 0.00 AC: 0 AN: 60268

GnomAD4 genome Cov.: 33

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	20
DANN	Benign	0.49
DEOGEN2	Benign	0.015	T
Eigen	Benign	0.044
Eigen_PC	Benign	0.023
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.62	T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.90	L
PhyloP100		4.3
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.35	N
REVEL	Benign	0.13
Sift	Uncertain	0.027	D
Sift4G	Benign	0.33	T
Vest4		0.46
MutPred		0.29		Gain of catalytic residue at F193 (P = 0.0419);
MVP		0.43
MPC		0.46
ClinPred		0.33	T
GERP RS		4.3
Varity_R		0.088
gMVP		0.21
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs782035854; hg19: chr12-208349;