10-13656687-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

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

Scores

1
9
9

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.93
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]
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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
FRMD4ANM_018027.5 linkc.2902G>A p.Val968Met missense_variant Exon 22 of 25 ENST00000357447.7 NP_060497.3 Q9P2Q2
FRMD4ANM_001318337.2 linkc.3001G>A p.Val1001Met missense_variant Exon 21 of 24 NP_001305266.1 Q9P2Q2
FRMD4ANM_001318336.2 linkc.2950G>A p.Val984Met missense_variant Exon 21 of 24 NP_001305265.1 Q9P2Q2Q9NW91
FRMD4ANM_001318338.2 linkc.1975G>A p.Val659Met missense_variant Exon 11 of 14 NP_001305267.1 Q9P2Q2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FRMD4AENST00000357447.7 linkc.2902G>A p.Val968Met missense_variant Exon 22 of 25 1 NM_018027.5 ENSP00000350032.2 Q9P2Q2
FRMD4AENST00000495956.3 linkc.2902G>A p.Val968Met missense_variant Exon 22 of 24 2 ENSP00000488764.2 A0A0J9YYA7
PRPF18ENST00000593351.2 linkn.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
show subpopulations
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
LINK: link

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

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

Other links and lift over

dbSNP: rs1415322494; hg19: chr10-13698687; API