10-13656906-G-A

Position:

chr10-13656906-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_018027.5(FRMD4A):c.2683C>T(p.Arg895Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000119 in 1,486,748 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R895H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000073 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

FRMD4A
NM_018027.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.90

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 links:

PRPF18 (HGNC:17351): (pre-mRNA processing factor 18) Pre-mRNA splicing occurs in 2 sequential transesterification steps. The protein encoded by this gene is found to be essential for the catalytic step II in pre-mRNA splicing process. It is found in the spliceosome, and contains seven WD repeats, which function in protein-protein interactions. This protein has a sequence similarity to the yeast splicing factor Prp18. [provided by RefSeq, Jul 2008]

PRPF18 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.768

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
FRMD4A	NM_018027.5 linkuse as main transcript	c.2683C>T	p.Arg895Cys	missense_variant	22/25	ENST00000357447.7
FRMD4A	NM_001318337.2 linkuse as main transcript	c.2782C>T	p.Arg928Cys	missense_variant	21/24
FRMD4A	NM_001318336.2 linkuse as main transcript	c.2731C>T	p.Arg911Cys	missense_variant	21/24
FRMD4A	NM_001318338.2 linkuse as main transcript	c.1756C>T	p.Arg586Cys	missense_variant	11/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
FRMD4A	ENST00000357447.7 linkuse as main transcript	c.2683C>T	p.Arg895Cys	missense_variant	22/25	1	NM_018027.5	P2
FRMD4A	ENST00000495956.3 linkuse as main transcript	c.2683C>T	p.Arg895Cys	missense_variant	22/24	2		A2
PRPF18	ENST00000593351.2 linkuse as main transcript	n.47+8676G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

AF:

0.0000727

AC:

AN:

151314

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000725

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000659

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000979

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000738

Gnomad OTH

AF:

0.000483

GnomAD3 exomes

AF:

0.000123

AC:

AN:

113744

Hom.:

AF XY:

0.000123

AC XY:

AN XY:

65238

show subpopulations

Gnomad AFR exome

AF:

0.000222

Gnomad AMR exome

AF:

0.0000607

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000164

Gnomad SAS exome

AF:

0.000176

Gnomad FIN exome

AF:

0.000153

Gnomad NFE exome

AF:

0.000129

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000124

AC:

166

AN:

1335434

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

659840

show subpopulations

Gnomad4 AFR exome

AF:

0.0000728

Gnomad4 AMR exome

AF:

0.000108

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000324

Gnomad4 SAS exome

AF:

0.0000819

Gnomad4 FIN exome

AF:

0.000140

Gnomad4 NFE exome

AF:

0.000129

Gnomad4 OTH exome

AF:

0.0000545

GnomAD4 genome

AF:

0.0000727

AC:

AN:

151314

Hom.:

Cov.:

AF XY:

0.0000947

AC XY:

AN XY:

73936

show subpopulations

Gnomad4 AFR

AF:

0.0000725

Gnomad4 AMR

AF:

0.0000659

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000979

Gnomad4 NFE

AF:

0.0000738

Gnomad4 OTH

AF:

0.000483

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.0000869

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000394

AC:

ExAC

AF:

0.000131

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 26, 2023

The c.2683C>T (p.R895C) alteration is located in exon 22 (coding exon 21) of the FRMD4A gene. This alteration results from a C to T substitution at nucleotide position 2683, causing the arginine (R) at amino acid position 895 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Pathogenic

0.22

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.047

Eigen

Uncertain

0.22

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.80

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.56

MetaRNN

Pathogenic

0.77

MetaSVM

Uncertain

0.18

MutationAssessor

Uncertain

2.0

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

-1.6

REVEL

Uncertain

0.56

Sift

Uncertain

0.0080

Sift4G

Uncertain

0.060

Polyphen

1.0

Vest4

0.80

MVP

0.87

MPC

1.3

ClinPred

0.071

GERP RS

4.9

Varity_R

0.24

gMVP

0.65

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over