NM_018027.5:c.46-127174C>T

Variant names:

• chr10-13986086-G-A
• rs2446585
• NM_018027.5:c.46-127174C>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.46-127174C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.523 in 152,002 control chromosomes in the GnomAD database, including 23,407 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 0.52 (23407 hom., cov: 30)
• Consequence: FRMD4A NM_018027.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.115
• 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=-0.96).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.877 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.46-127174C>T		intron	N/A	NP_060497.3
	FRMD4A	NM_001318336.2		c.93+21974C>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.46-127174C>T		intron	N/A	ENSP00000350032.2
	FRMD4A	ENST00000495956.3	TSL:2	c.46-127174C>T		intron	N/A	ENSP00000488764.2
	FRMD4A	ENST00000640906.1	TSL:4	c.93+21974C>T		intron	N/A	ENSP00000492091.1

Frequencies

GnomAD3 genomes AF: 0.522 AC: 79334 AN: 151884 Hom.: 23369 Cov.: 30

Gnomad AFR AF: 0.754

Gnomad AMI AF: 0.283

Gnomad AMR AF: 0.595

Gnomad ASJ AF: 0.490

Gnomad EAS AF: 0.899

Gnomad SAS AF: 0.618

Gnomad FIN AF: 0.311

Gnomad MID AF: 0.500

Gnomad NFE AF: 0.368

Gnomad OTH AF: 0.526

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

GnomAD4 genome AF: 0.523 AC: 79429 AN: 152002 Hom.: 23407 Cov.: 30 AF XY: 0.526 AC XY: 39078 AN XY: 74270

African (AFR) AF: 0.754 AC: 31261 AN: 41472

American (AMR) AF: 0.596 AC: 9103 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.490 AC: 1697 AN: 3464

East Asian (EAS) AF: 0.899 AC: 4616 AN: 5134

South Asian (SAS) AF: 0.617 AC: 2965 AN: 4808

European-Finnish (FIN) AF: 0.311 AC: 3286 AN: 10574

Middle Eastern (MID) AF: 0.490 AC: 144 AN: 294

European-Non Finnish (NFE) AF: 0.368 AC: 24977 AN: 67954

Other (OTH) AF: 0.531 AC: 1122 AN: 2112

Alfa AF: 0.457 Hom.: 7514

Bravo AF: 0.554

Asia WGS AF: 0.771 AC: 2680 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.87
DANN	Benign	0.32
PhyloP100		-0.12
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: rs2446585; hg19: chr10-14028086;