10-14405340-T-C

Variant names:

• chr10-14405340-T-C
• rs649364
• ENST00000475141.2:c.-304-16437A>G

Variant summary

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

The ENST00000475141.2(FRMD4A):​c.-304-16437A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.257 in 152,100 control chromosomes in the GnomAD database, including 5,642 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 0.26 (5642 hom., cov: 32)
• Consequence: FRMD4A ENST00000475141.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.16
• Publications: 2 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]

FRMD4A Gene-Disease associations (from GenCC):

• severe intellectual disability-corpus callosum agenesis-facial dysmorphism-cerebellar ataxia syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.582 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FRMD4A	ENST00000475141.2	c.-304-16437A>G		intron_variant	Intron 1 of 3	1		ENSP00000473870.1
FRMD4A	ENST00000493380.5	c.-82+56728A>G		intron_variant	Intron 1 of 3	1		ENSP00000474863.1

Frequencies

GnomAD3 genomes AF: 0.257 AC: 39112 AN: 151982 Hom.: 5629 Cov.: 32

Gnomad AFR AF: 0.201

Gnomad AMI AF: 0.179

Gnomad AMR AF: 0.340

Gnomad ASJ AF: 0.184

Gnomad EAS AF: 0.600

Gnomad SAS AF: 0.369

Gnomad FIN AF: 0.198

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.253

Gnomad OTH AF: 0.267

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.257 AC: 39150 AN: 152100 Hom.: 5642 Cov.: 32 AF XY: 0.259 AC XY: 19244 AN XY: 74342

African (AFR) AF: 0.201 AC: 8324 AN: 41478

American (AMR) AF: 0.340 AC: 5198 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.184 AC: 638 AN: 3472

East Asian (EAS) AF: 0.600 AC: 3102 AN: 5172

South Asian (SAS) AF: 0.369 AC: 1779 AN: 4818

European-Finnish (FIN) AF: 0.198 AC: 2090 AN: 10582

Middle Eastern (MID) AF: 0.204 AC: 60 AN: 294

European-Non Finnish (NFE) AF: 0.253 AC: 17222 AN: 67990

Other (OTH) AF: 0.272 AC: 574 AN: 2108

Alfa AF: 0.236 Hom.: 2289

Bravo AF: 0.265

Asia WGS AF: 0.458 AC: 1591 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.53
DANN	Benign	0.41
PhyloP100		-1.2
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: rs649364; hg19: chr10-14447339;