chr12-125634-G-T

Variant names:

• chr12-125634-G-T
• rs368059304
• NM_001170738.2:c.625G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001170738.2(IQSEC3):​c.625G>T​(p.Asp209Tyr) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000865 in 1,502,424 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000044 (0 hom.)
• Consequence: IQSEC3 NM_001170738.2 missense, splice_region
• Scores: Splicing: ADA: 0.9801
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.61
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IQSEC3	NM_001170738.2	c.625G>T	p.Asp209Tyr	missense_variant, splice_region_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.625G>T	p.Asp209Tyr	missense_variant, splice_region_variant	Exon 3 of 14	5	NM_001170738.2	ENSP00000437554.1
IQSEC3	ENST00000382841.2	c.-6-12633G>T		intron_variant	Intron 2 of 12	2		ENSP00000372292.2

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152236 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000169

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000140 AC: 2 AN: 142530 AF XY: 0.00

Gnomad AFR exome AF: 0.000220

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000444 AC: 6 AN: 1350188 Hom.: 0 Cov.: 30 AF XY: 0.00000452 AC XY: 3 AN XY: 664426

African (AFR) AF: 0.000216 AC: 6 AN: 27758

American (AMR) AF: 0.00 AC: 0 AN: 29542

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19844

East Asian (EAS) AF: 0.00 AC: 0 AN: 36352

South Asian (SAS) AF: 0.00 AC: 0 AN: 70428

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34866

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5352

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1069966

Other (OTH) AF: 0.00 AC: 0 AN: 56080

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152236 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74376

African (AFR) AF: 0.000169 AC: 7 AN: 41464

American (AMR) AF: 0.00 AC: 0 AN: 15290

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68046

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

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000793

ESP6500AA AF: 0.000344 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000256 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 18, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.625G>T (p.D209Y) alteration is located in exon 3 (coding exon 3) of the IQSEC3 gene. This alteration results from a G to T substitution at nucleotide position 625, causing the aspartic acid (D) at amino acid position 209 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.030	T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.73	T
M_CAP	Pathogenic	0.35	D
MetaRNN	Uncertain	0.69	D
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	0.90	L
PhyloP100		6.6
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-2.5	N
REVEL	Uncertain	0.37
Sift	Uncertain	0.0030	D
Sift4G	Benign	0.066	T
Vest4		0.70
MVP		0.72
MPC		1.2
ClinPred		0.69	D
GERP RS		5.4
Varity_R		0.50
gMVP		0.41
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.98
dbscSNV1_RF	Pathogenic	0.82
SpliceAI score (max)		0.010		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: rs368059304; hg19: chr12-234800;