rs12220909

Positions:

• chr10-14383222-G-C
• chr10-14383222-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000475141.2(FRMD4A):​c.-82+5459C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0116 in 154,786 control chromosomes in the GnomAD database, including 82 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.012 (82 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (0 hom.)
• Consequence: FRMD4A ENST00000475141.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.469

Genes affected

FRMD4A (HGNC:25491): (FERM domain containing 4A) This gene encodes a FERM domain-containing protein that regulates epithelial cell polarity. It connects ADP ribosylation factor 6 (ARF6) with the Par protein complex, which regulates the remodeling of adherens junctions and linear actin cable formation during epithelial cell polarization. Polymorphisms in this gene are associated with Alzheimer's disease, and also with nicotine dependence. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2015]

MIR4293 (HGNC:38270): (microRNA 4293) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.127 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MIR4293	NR_036181.1	n.56C>G		non_coding_transcript_exon_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FRMD4A	ENST00000475141.2	c.-82+5459C>G		intron_variant		1		ENSP00000473870
FRMD4A	ENST00000493380.5	c.-81-53039C>G		intron_variant		1		ENSP00000474863
MIR4293	ENST00000584305.1	n.56C>G		mature_miRNA_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.0118 AC: 1788 AN: 152144 Hom.: 82 Cov.: 32

Gnomad AFR AF: 0.00362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0364

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.136

Gnomad SAS AF: 0.0160

Gnomad FIN AF: 0.00386

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00298

Gnomad OTH AF: 0.0191

GnomAD3 exomes AF: 0.00487 AC: 31 AN: 6364 Hom.: 2 AF XY: 0.00455 AC XY: 14 AN XY: 3078

Gnomad AFR exome AF: 0.00562

Gnomad AMR exome AF: 0.0431

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0972

Gnomad SAS exome AF: 0.00

Gnomad NFE exome AF: 0.00261

Gnomad OTH exome AF: 0.0208

GnomAD4 exome AF: 0.00317 AC: 8 AN: 2524 Hom.: 0 Cov.: 0 AF XY: 0.00307 AC XY: 4 AN XY: 1302

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 SAS exome AF: 0.0109

Gnomad4 FIN exome AF: 0.00469

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0118 AC: 1791 AN: 152262 Hom.: 82 Cov.: 32 AF XY: 0.0128 AC XY: 949 AN XY: 74430

Gnomad4 AFR AF: 0.00361

Gnomad4 AMR AF: 0.0365

Gnomad4 ASJ AF: 0.00490

Gnomad4 EAS AF: 0.136

Gnomad4 SAS AF: 0.0162

Gnomad4 FIN AF: 0.00386

Gnomad4 NFE AF: 0.00298

Gnomad4 OTH AF: 0.0199

Alfa AF: 0.000750 Hom.: 0

Bravo AF: 0.0178

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	10
DANN	Benign	0.83

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs12220909; hg19: chr10-14425221;