12-67212-T-C

Variant names:

• chr12-67212-T-C
• rs781928254
• NM_001170738.2:c.330T>C

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM2 BP4_Strong BP6_Very_Strong BP7

The NM_001170738.2(IQSEC3):​c.330T>C​(p.Asp110Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00769 in 150,130 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 0.0077 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00083 (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: 1.61
• 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: Benign. The variant received -11 ACMG points.

• PM2: Variant has high frequency in the AFR (0.0263) population. However there is too low homozygotes in high coverage region: (expected more than 2, got 0).
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 12-67212-T-C is Benign according to our data. Variant chr12-67212-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 783652.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.62 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IQSEC3	NM_001170738.2	c.330T>C	p.Asp110Asp	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.330T>C	p.Asp110Asp	synonymous_variant	Exon 1 of 14	5	NM_001170738.2	ENSP00000437554.1

Frequencies

GnomAD3 genomes AF: 0.00769 AC: 1154 AN: 150010 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0277

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00270

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00680

GnomAD2 exomes AF: 0.00304 AC: 417 AN: 137128 AF XY: 0.00252

Gnomad AFR exome AF: 0.0512

Gnomad AMR exome AF: 0.00233

Gnomad ASJ exome AF: 0.00159

Gnomad EAS exome AF: 0.0000915

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000128

Gnomad OTH exome AF: 0.00120

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000826 AC: 1160 AN: 1405072 Hom.: 0 Cov.: 36 AF XY: 0.000724 AC XY: 504 AN XY: 696334

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

African (AFR) AF: 0.0309 AC: 942 AN: 30460

American (AMR) AF: 0.00188 AC: 73 AN: 38866

Ashkenazi Jewish (ASJ) AF: 0.000631 AC: 16 AN: 25340

East Asian (EAS) AF: 0.0000533 AC: 2 AN: 37524

South Asian (SAS) AF: 0.0000245 AC: 2 AN: 81632

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35538

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4170

European-Non Finnish (NFE) AF: 0.0000485 AC: 53 AN: 1093176

Other (OTH) AF: 0.00123 AC: 72 AN: 58366

⚠️ 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: 0.00769 AC: 1155 AN: 150130 Hom.: 0 Cov.: 34 AF XY: 0.00721 AC XY: 529 AN XY: 73418

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

African (AFR) AF: 0.0277 AC: 1094 AN: 39518

American (AMR) AF: 0.00270 AC: 41 AN: 15208

Ashkenazi Jewish (ASJ) AF: 0.000289 AC: 1 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68022

Other (OTH) AF: 0.00672 AC: 14 AN: 2082

⚠️ 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: 0.00657 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jan 03, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	9.7
DANN	Benign	0.50
PhyloP100		1.6
PromoterAI		-0.0074	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs781928254; hg19: chr12-176378;