chr10-13876753-T-C

Variant names:

• chr10-13876753-T-C
• rs10508468
• NM_018027.5:c.46-17841A>G

Variant summary

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

The NM_018027.5(FRMD4A):​c.46-17841A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.291 in 151,838 control chromosomes in the GnomAD database, including 7,056 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 0.29 (7056 hom., cov: 32)
• Consequence: FRMD4A NM_018027.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.53
• 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]

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=-0.92).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.365 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FRMD4A	NM_018027.5	c.46-17841A>G		intron_variant	Intron 2 of 24	ENST00000357447.7	NP_060497.3
FRMD4A	NM_001318337.2	c.145-17841A>G		intron_variant	Intron 1 of 23		NP_001305266.1
FRMD4A	NM_001318336.2	c.94-17841A>G		intron_variant	Intron 1 of 23		NP_001305265.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FRMD4A	ENST00000357447.7	c.46-17841A>G		intron_variant	Intron 2 of 24	1	NM_018027.5	ENSP00000350032.2

Frequencies

GnomAD3 genomes AF: 0.291 AC: 44221 AN: 151724 Hom.: 7058 Cov.: 32

Gnomad AFR AF: 0.173

Gnomad AMI AF: 0.337

Gnomad AMR AF: 0.261

Gnomad ASJ AF: 0.340

Gnomad EAS AF: 0.346

Gnomad SAS AF: 0.188

Gnomad FIN AF: 0.311

Gnomad MID AF: 0.269

Gnomad NFE AF: 0.368

Gnomad OTH AF: 0.263

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

GnomAD4 genome AF: 0.291 AC: 44221 AN: 151838 Hom.: 7056 Cov.: 32 AF XY: 0.284 AC XY: 21068 AN XY: 74230

African (AFR) AF: 0.173 AC: 7165 AN: 41468

American (AMR) AF: 0.261 AC: 3970 AN: 15226

Ashkenazi Jewish (ASJ) AF: 0.340 AC: 1179 AN: 3470

East Asian (EAS) AF: 0.346 AC: 1786 AN: 5168

South Asian (SAS) AF: 0.189 AC: 909 AN: 4820

European-Finnish (FIN) AF: 0.311 AC: 3250 AN: 10452

Middle Eastern (MID) AF: 0.281 AC: 82 AN: 292

European-Non Finnish (NFE) AF: 0.368 AC: 25030 AN: 67932

Other (OTH) AF: 0.259 AC: 544 AN: 2102

Alfa AF: 0.338 Hom.: 17630

Bravo AF: 0.289

Asia WGS AF: 0.269 AC: 937 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.0040
DANN	Benign	0.52
PhyloP100		-3.5
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs10508468; hg19: chr10-13918753;