NM_018027.5:c.46-90953C>T

Variant names:

• chr10-13949865-G-A
• rs7081208
• NM_018027.5:c.46-90953C>T

Variant summary

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

The NM_018027.5(FRMD4A):​c.46-90953C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.183 in 152,234 control chromosomes in the GnomAD database, including 3,197 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 0.18 (3197 hom., cov: 32)
• Consequence: FRMD4A NM_018027.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.76
• Publications: 22 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=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.269 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FRMD4A	NM_018027.5	c.46-90953C>T		intron_variant	Intron 2 of 24	ENST00000357447.7	NP_060497.3
FRMD4A	NM_001318337.2	c.144+21791C>T		intron_variant	Intron 1 of 23		NP_001305266.1
FRMD4A	NM_001318336.2	c.93+58195C>T		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.46-90953C>T		intron_variant	Intron 2 of 24	1	NM_018027.5	ENSP00000350032.2

Frequencies

GnomAD3 genomes AF: 0.183 AC: 27814 AN: 152116 Hom.: 3198 Cov.: 32

Gnomad AFR AF: 0.0705

Gnomad AMI AF: 0.218

Gnomad AMR AF: 0.128

Gnomad ASJ AF: 0.180

Gnomad EAS AF: 0.0244

Gnomad SAS AF: 0.159

Gnomad FIN AF: 0.213

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.272

Gnomad OTH AF: 0.184

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

GnomAD4 genome AF: 0.183 AC: 27802 AN: 152234 Hom.: 3197 Cov.: 32 AF XY: 0.178 AC XY: 13272 AN XY: 74416

African (AFR) AF: 0.0703 AC: 2921 AN: 41542

American (AMR) AF: 0.128 AC: 1953 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.180 AC: 625 AN: 3468

East Asian (EAS) AF: 0.0243 AC: 126 AN: 5194

South Asian (SAS) AF: 0.158 AC: 764 AN: 4830

European-Finnish (FIN) AF: 0.213 AC: 2253 AN: 10586

Middle Eastern (MID) AF: 0.201 AC: 59 AN: 294

European-Non Finnish (NFE) AF: 0.272 AC: 18519 AN: 68004

Other (OTH) AF: 0.182 AC: 384 AN: 2110

Alfa AF: 0.236 Hom.: 20671

Bravo AF: 0.168

Asia WGS AF: 0.0950 AC: 332 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.018
DANN	Benign	0.72
PhyloP100		-1.8
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: rs7081208; hg19: chr10-13991865;