Variant chr10-13656890-C-T details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_018027.5(FRMD4A):c.2699G>A(p.Arg900Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000151 in 1,327,392 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 (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

FRMD4A
NM_018027.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.42

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:

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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, 0.781

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FRMD4A	NM_018027.5 link	c.2699G>A	p.Arg900Gln	missense_variant	22/25	ENST00000357447.7	NP_060497.3	Q9P2Q2
FRMD4A	NM_001318337.2 link	c.2798G>A	p.Arg933Gln	missense_variant	21/24		NP_001305266.1	Q9P2Q2
FRMD4A	NM_001318336.2 link	c.2747G>A	p.Arg916Gln	missense_variant	21/24		NP_001305265.1	Q9P2Q2Q9NW91
FRMD4A	NM_001318338.2 link	c.1772G>A	p.Arg591Gln	missense_variant	11/14		NP_001305267.1	Q9P2Q2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
FRMD4A	ENST00000357447.7 link	c.2699G>A	p.Arg900Gln	missense_variant	22/25	1	NM_018027.5	ENSP00000350032.2	Q9P2Q2
FRMD4A	ENST00000495956.3 link	c.2699G>A	p.Arg900Gln	missense_variant	22/24	2		ENSP00000488764.2	A0A0J9YYA7
PRPF18	ENST00000593351.2 link	n.47+8660C>T		intron_variant		5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000151

AC:

AN:

1327392

Hom.:

Cov.:

AF XY:

0.00000153

AC XY:

AN XY:

654338

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000280

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

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 16, 2024

The c.2699G>A (p.R900Q) alteration is located in exon 22 (coding exon 21) of the FRMD4A gene. This alteration results from a G to A substitution at nucleotide position 2699, causing the arginine (R) at amino acid position 900 to be replaced by a glutamine (Q). 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

Uncertain

0.48

BayesDel_addAF

Uncertain

0.086

BayesDel_noAF

Benign

-0.11

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.028

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.96

M_CAP

Pathogenic

0.49

MetaRNN

Pathogenic

0.78

MetaSVM

Uncertain

0.016

MutationAssessor

Benign

1.4

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-0.98

REVEL

Uncertain

0.39

Sift

Benign

0.31

Sift4G

Benign

0.33

Polyphen

1.0

Vest4

0.61

MutPred

0.23

Loss of MoRF binding (P = 0.0587);

MVP

0.80

MPC

0.71

ClinPred

0.91

GERP RS

4.9

Varity_R

0.28

gMVP

0.61

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over