NM_018027.5:c.46-107533C>T

Variant names:

• chr10-13966445-G-A
• rs2446581
• NM_018027.5:c.46-107533C>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.46-107533C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.274 in 152,178 control chromosomes in the GnomAD database, including 9,041 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 0.27 (9041 hom., cov: 33)
• Consequence: FRMD4A NM_018027.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0380
• Publications: 15 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=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.597 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018027.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FRMD4A	NM_018027.5	MANE Select	c.46-107533C>T		intron	N/A	NP_060497.3
	FRMD4A	NM_001318337.2		c.144+5211C>T		intron	N/A	NP_001305266.1
	FRMD4A	NM_001318336.2		c.93+41615C>T		intron	N/A	NP_001305265.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FRMD4A	ENST00000357447.7	TSL:1 MANE Select	c.46-107533C>T		intron	N/A	ENSP00000350032.2
	FRMD4A	ENST00000495956.3	TSL:2	c.46-107533C>T		intron	N/A	ENSP00000488764.2
	FRMD4A	ENST00000264546.10	TSL:2	c.144+5211C>T		intron	N/A	ENSP00000264546.6

Frequencies

GnomAD3 genomes AF: 0.274 AC: 41639 AN: 152058 Hom.: 9027 Cov.: 33

Gnomad AFR AF: 0.603

Gnomad AMI AF: 0.185

Gnomad AMR AF: 0.259

Gnomad ASJ AF: 0.147

Gnomad EAS AF: 0.275

Gnomad SAS AF: 0.144

Gnomad FIN AF: 0.149

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.115

Gnomad OTH AF: 0.235

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

GnomAD4 genome AF: 0.274 AC: 41721 AN: 152178 Hom.: 9041 Cov.: 33 AF XY: 0.274 AC XY: 20405 AN XY: 74390

African (AFR) AF: 0.603 AC: 25012 AN: 41490

American (AMR) AF: 0.259 AC: 3967 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.147 AC: 512 AN: 3472

East Asian (EAS) AF: 0.276 AC: 1427 AN: 5176

South Asian (SAS) AF: 0.143 AC: 691 AN: 4828

European-Finnish (FIN) AF: 0.149 AC: 1576 AN: 10580

Middle Eastern (MID) AF: 0.160 AC: 47 AN: 294

European-Non Finnish (NFE) AF: 0.115 AC: 7813 AN: 68018

Other (OTH) AF: 0.240 AC: 507 AN: 2114

Alfa AF: 0.160 Hom.: 13812

Bravo AF: 0.298

Asia WGS AF: 0.235 AC: 816 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.60
DANN	Benign	0.86
PhyloP100		0.038
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: rs2446581; hg19: chr10-14008445;