10-14436619-T-C

Variant names:

• chr10-14436619-T-C
• rs11259096
• ENST00000475141.2:c.-305+25449A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000475141.2(FRMD4A):​c.-305+25449A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.069 in 514,240 control chromosomes in the GnomAD database, including 2,264 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 0.10 (1413 hom., cov: 31)
  • Exomes 𝑓: 0.054 (851 hom.)
• Consequence: FRMD4A ENST00000475141.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.688
• Publications: 13 publications found

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]

MIR1265 (HGNC:35332): (microRNA 1265) 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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.248 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000475141.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MIR1265	NR_031668.1		n.44T>C		non_coding_transcript_exon	Exon 1 of 1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FRMD4A	ENST00000475141.2	TSL:1	c.-305+25449A>G		intron	N/A	ENSP00000473870.1	S4R324
	FRMD4A	ENST00000493380.5	TSL:1	c.-82+25449A>G		intron	N/A	ENSP00000474863.1	S4R3Y6
	MIR1265	ENST00000408444.1	TSL:6	n.44T>C		non_coding_transcript_exon	Exon 1 of 1

Frequencies

GnomAD3 genomes AF: 0.104 AC: 15787 AN: 152020 Hom.: 1409 Cov.: 31

Gnomad AFR AF: 0.252

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0605

Gnomad ASJ AF: 0.0565

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0577

Gnomad FIN AF: 0.0389

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0496

Gnomad OTH AF: 0.0790

GnomAD2 exomes AF: 0.0579 AC: 12488 AN: 215620 AF XY: 0.0571

Gnomad AFR exome AF: 0.256

Gnomad AMR exome AF: 0.0336

Gnomad ASJ exome AF: 0.0541

Gnomad EAS exome AF: 0.000297

Gnomad FIN exome AF: 0.0392

Gnomad NFE exome AF: 0.0514

Gnomad OTH exome AF: 0.0560

GnomAD4 exome AF: 0.0544 AC: 19690 AN: 362102 Hom.: 851 Cov.: 0 AF XY: 0.0544 AC XY: 11171 AN XY: 205368

African (AFR) AF: 0.253 AC: 2569 AN: 10164

American (AMR) AF: 0.0340 AC: 1168 AN: 34382

Ashkenazi Jewish (ASJ) AF: 0.0543 AC: 607 AN: 11172

East Asian (EAS) AF: 0.000311 AC: 4 AN: 12864

South Asian (SAS) AF: 0.0629 AC: 3975 AN: 63240

European-Finnish (FIN) AF: 0.0389 AC: 1211 AN: 31154

Middle Eastern (MID) AF: 0.117 AC: 289 AN: 2476

European-Non Finnish (NFE) AF: 0.0494 AC: 8923 AN: 180784

Other (OTH) AF: 0.0595 AC: 944 AN: 15866

GnomAD4 genome AF: 0.104 AC: 15811 AN: 152138 Hom.: 1413 Cov.: 31 AF XY: 0.102 AC XY: 7555 AN XY: 74376

African (AFR) AF: 0.252 AC: 10442 AN: 41456

American (AMR) AF: 0.0604 AC: 923 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0565 AC: 196 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.0571 AC: 275 AN: 4818

European-Finnish (FIN) AF: 0.0389 AC: 413 AN: 10604

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.0496 AC: 3373 AN: 68004

Other (OTH) AF: 0.0782 AC: 165 AN: 2110

Alfa AF: 0.0722 Hom.: 1105

Bravo AF: 0.112

Asia WGS AF: 0.0390 AC: 136 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.7
DANN	Benign	0.51
PhyloP100		0.69
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs11259096; hg19: chr10-14478618;