Genetic Variant FRMD4A:c.*190T>A (chr10-14083636-A-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000493380.5(FRMD4A):c.*190T>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.227 in 152,156 control chromosomes in the GnomAD database, including 4,174 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 0.23 ( 4173 hom., cov: 33)

Exomes 𝑓: 0.18 ( 1 hom. )

Consequence

FRMD4A
ENST00000493380.5 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.45

Publications

4 publications found

Variant links:

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

FRMD4A links:

ENSG00000235410 (HGNC:58386):

ENSG00000235410 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.364 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
FRMD4A	NM_018027.5 link	c.46-224724T>A	intron_variant	Intron 2 of 24	ENST00000357447.7	NP_060497.3
FRMD4A	NR_134578.2 link	n.761T>A	non_coding_transcript_exon_variant	Exon 4 of 4
FRMD4A-AS3	NR_120638.1 link	n.699+183A>T	intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FRMD4A	ENST00000357447.7 link	c.46-224724T>A		intron_variant	Intron 2 of 24	1	NM_018027.5	ENSP00000350032.2

Frequencies

GnomAD3 genomes

AF:

0.227

AC:

34479

AN:

152010

Hom.:

4171

Cov.:

show subpopulations

Gnomad AFR

AF:

0.152

Gnomad AMI

AF:

0.257

Gnomad AMR

AF:

0.286

Gnomad ASJ

AF:

0.348

Gnomad EAS

AF:

0.378

Gnomad SAS

AF:

0.243

Gnomad FIN

AF:

0.238

Gnomad MID

AF:

0.234

Gnomad NFE

AF:

0.238

Gnomad OTH

AF:

0.225

GnomAD4 exome

AF:

0.179

AC:

AN:

Hom.:

Cov.:

AF XY:

0.182

AC XY:

AN XY:

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.208

AC:

AN:

Other (OTH)

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.592

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.227

AC:

34499

AN:

152128

Hom.:

4173

Cov.:

AF XY:

0.231

AC XY:

17180

AN XY:

74366

show subpopulations

African (AFR)

AF:

0.152

AC:

6327

AN:

41508

American (AMR)

AF:

0.287

AC:

4383

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.348

AC:

1207

AN:

3466

East Asian (EAS)

AF:

0.377

AC:

1947

AN:

5158

South Asian (SAS)

AF:

0.242

AC:

1166

AN:

4826

European-Finnish (FIN)

AF:

0.238

AC:

2515

AN:

10578

Middle Eastern (MID)

AF:

0.228

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.238

AC:

16169

AN:

67984

Other (OTH)

AF:

0.230

AC:

485

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1392

2784

4176

5568

6960

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

358

716

1074

1432

1790

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.222

Hom.:

461

Bravo

AF:

0.227

Asia WGS

AF:

0.289

AC:

1003

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

6.7

(source)

DANN

Benign

0.59

PhyloP100

1.4

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over