NM_018027.5:c.464+2378T>C

Variant names:

• chr10-13759269-A-G
• rs4424567
• NM_018027.5:c.464+2378T>C

Variant summary

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

The NM_018027.5(FRMD4A):​c.464+2378T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.255 in 152,152 control chromosomes in the GnomAD database, including 5,670 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 0.25 (5670 hom., cov: 32)
• Consequence: FRMD4A NM_018027.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.34
• Publications: 3 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=-0.64).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.526 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FRMD4A	NM_018027.5	c.464+2378T>C		intron_variant	Intron 8 of 24	ENST00000357447.7	NP_060497.3
FRMD4A	NM_001318337.2	c.563+2378T>C		intron_variant	Intron 7 of 23		NP_001305266.1
FRMD4A	NM_001318336.2	c.512+2378T>C		intron_variant	Intron 7 of 23		NP_001305265.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FRMD4A	ENST00000357447.7	c.464+2378T>C		intron_variant	Intron 8 of 24	1	NM_018027.5	ENSP00000350032.2

Frequencies

GnomAD3 genomes AF: 0.255 AC: 38751 AN: 152032 Hom.: 5674 Cov.: 32

Gnomad AFR AF: 0.166

Gnomad AMI AF: 0.0833

Gnomad AMR AF: 0.380

Gnomad ASJ AF: 0.234

Gnomad EAS AF: 0.544

Gnomad SAS AF: 0.382

Gnomad FIN AF: 0.209

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.260

Gnomad OTH AF: 0.269

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

GnomAD4 genome AF: 0.255 AC: 38759 AN: 152152 Hom.: 5670 Cov.: 32 AF XY: 0.258 AC XY: 19194 AN XY: 74388

African (AFR) AF: 0.166 AC: 6887 AN: 41516

American (AMR) AF: 0.380 AC: 5807 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.234 AC: 811 AN: 3470

East Asian (EAS) AF: 0.543 AC: 2809 AN: 5172

South Asian (SAS) AF: 0.383 AC: 1843 AN: 4816

European-Finnish (FIN) AF: 0.209 AC: 2219 AN: 10594

Middle Eastern (MID) AF: 0.231 AC: 68 AN: 294

European-Non Finnish (NFE) AF: 0.260 AC: 17677 AN: 67990

Other (OTH) AF: 0.266 AC: 562 AN: 2112

Alfa AF: 0.267 Hom.: 24016

Bravo AF: 0.263

Asia WGS AF: 0.429 AC: 1495 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	11
DANN	Benign	0.56
PhyloP100		1.3
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: rs4424567; hg19: chr10-13801269;