NM_018027.5:c.46-117856T>G

Variant names:

• chr10-13976768-A-C
• rs4237438
• NM_018027.5:c.46-117856T>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.46-117856T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.355 in 152,124 control chromosomes in the GnomAD database, including 9,954 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 0.35 (9954 hom., cov: 32)
• Consequence: FRMD4A NM_018027.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.11
• Publications: 1 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=-0.85).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.585 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FRMD4A	NM_018027.5	c.46-117856T>G		intron_variant	Intron 2 of 24	ENST00000357447.7	NP_060497.3
FRMD4A	NM_001318336.2	c.93+31292T>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.46-117856T>G		intron_variant	Intron 2 of 24	1	NM_018027.5	ENSP00000350032.2

Frequencies

GnomAD3 genomes AF: 0.355 AC: 53950 AN: 152004 Hom.: 9952 Cov.: 32

Gnomad AFR AF: 0.358

Gnomad AMI AF: 0.243

Gnomad AMR AF: 0.389

Gnomad ASJ AF: 0.413

Gnomad EAS AF: 0.603

Gnomad SAS AF: 0.517

Gnomad FIN AF: 0.271

Gnomad MID AF: 0.415

Gnomad NFE AF: 0.326

Gnomad OTH AF: 0.372

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

GnomAD4 genome AF: 0.355 AC: 53988 AN: 152124 Hom.: 9954 Cov.: 32 AF XY: 0.355 AC XY: 26410 AN XY: 74366

African (AFR) AF: 0.358 AC: 14866 AN: 41480

American (AMR) AF: 0.389 AC: 5944 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.413 AC: 1432 AN: 3470

East Asian (EAS) AF: 0.603 AC: 3121 AN: 5180

South Asian (SAS) AF: 0.518 AC: 2498 AN: 4826

European-Finnish (FIN) AF: 0.271 AC: 2863 AN: 10582

Middle Eastern (MID) AF: 0.384 AC: 113 AN: 294

European-Non Finnish (NFE) AF: 0.326 AC: 22142 AN: 67982

Other (OTH) AF: 0.373 AC: 787 AN: 2112

Alfa AF: 0.202 Hom.: 439

Bravo AF: 0.361

Asia WGS AF: 0.569 AC: 1977 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	6.5
DANN	Benign	0.35
PhyloP100		2.1
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: rs4237438; hg19: chr10-14018768;