chr12-67206-G-A

Variant names:

• chr12-67206-G-A
• rs782213176
• NM_001170738.2:c.324G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BP6_Very_Strong

The NM_001170738.2(IQSEC3):​c.324G>A​(p.Ala108Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000807 in 152,336 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00081 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00084 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: IQSEC3 NM_001170738.2 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.193
• 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: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 12-67206-G-A is Benign according to our data. Variant chr12-67206-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 732536.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IQSEC3	NM_001170738.2	c.324G>A	p.Ala108Ala	synonymous_variant	Exon 1 of 14	ENST00000538872.6	NP_001164209.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IQSEC3	ENST00000538872.6	c.324G>A	p.Ala108Ala	synonymous_variant	Exon 1 of 14	5	NM_001170738.2	ENSP00000437554.1

Frequencies

GnomAD3 genomes AF: 0.000808 AC: 123 AN: 152218 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00116

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000779 AC: 105 AN: 134870 AF XY: 0.000747

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00140

Gnomad ASJ exome AF: 0.00172

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000994

Gnomad OTH exome AF: 0.000978

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000841 AC: 1179 AN: 1402374 Hom.: 0 Cov.: 36 AF XY: 0.000858 AC XY: 596 AN XY: 694438

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000125 AC: 4 AN: 31950

American (AMR) AF: 0.00131 AC: 50 AN: 38272

Ashkenazi Jewish (ASJ) AF: 0.00233 AC: 59 AN: 25332

East Asian (EAS) AF: 0.00 AC: 0 AN: 37168

South Asian (SAS) AF: 0.00 AC: 0 AN: 81222

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35260

Middle Eastern (MID) AF: 0.00121 AC: 5 AN: 4136

European-Non Finnish (NFE) AF: 0.000923 AC: 1007 AN: 1090614

Other (OTH) AF: 0.000924 AC: 54 AN: 58420

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000807 AC: 123 AN: 152336 Hom.: 0 Cov.: 34 AF XY: 0.000765 AC XY: 57 AN XY: 74500

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000962 AC: 4 AN: 41576

American (AMR) AF: 0.00196 AC: 30 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00230 AC: 8 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00116 AC: 79 AN: 68020

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000577 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

May 31, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	1.2
DANN	Benign	0.90
PhyloP100		-0.19
PromoterAI		0.013	Neutral
Mutation Taster		=99/1	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs782213176; hg19: chr12-176372;