10-13656687-C-T

Variant names:

• chr10-13656687-C-T
• rs1415322494
• NM_018027.5:c.2902G>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_018027.5(FRMD4A):​c.2902G>A​(p.Val968Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000285 in 1,403,842 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: FRMD4A NM_018027.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.93

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]

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35344484).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FRMD4A	NM_018027.5	c.2902G>A	p.Val968Met	missense_variant	Exon 22 of 25	ENST00000357447.7	NP_060497.3
FRMD4A	NM_001318337.2	c.3001G>A	p.Val1001Met	missense_variant	Exon 21 of 24		NP_001305266.1
FRMD4A	NM_001318336.2	c.2950G>A	p.Val984Met	missense_variant	Exon 21 of 24		NP_001305265.1
FRMD4A	NM_001318338.2	c.1975G>A	p.Val659Met	missense_variant	Exon 11 of 14		NP_001305267.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FRMD4A	ENST00000357447.7	c.2902G>A	p.Val968Met	missense_variant	Exon 22 of 25	1	NM_018027.5	ENSP00000350032.2
FRMD4A	ENST00000495956.3	c.2902G>A	p.Val968Met	missense_variant	Exon 22 of 24	2		ENSP00000488764.2
PRPF18	ENST00000593351.2	n.47+8457C>T		intron_variant	Intron 1 of 2	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000285 AC: 4 AN: 1403842 Hom.: 0 Cov.: 31 AF XY: 0.00000287 AC XY: 2 AN XY: 697208

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000261

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000185

Gnomad4 OTH exome AF: 0.0000173

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 26, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2902G>A (p.V968M) 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 2902, causing the valine (V) at amino acid position 968 to be replaced by a methionine (M). 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	0.12
BayesDel_addAF	Uncertain	0.064	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.021	T
Eigen	Benign	0.029
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.087	D
MetaRNN	Benign	0.35	T
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Benign	1.5	L
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.79	N
REVEL	Uncertain	0.42
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.046	D
Polyphen		0.89	P
Vest4		0.52
MutPred		0.27		Loss of sheet (P = 0.0043);
MVP		0.51
MPC		0.47
ClinPred		0.33	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.27
gMVP		0.31

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

Other links and lift over

dbSNP: rs1415322494; hg19: chr10-13698687;