10-13654499-T-G

Variant names:

• chr10-13654499-T-G
• rs1017080215
• NM_018027.5:c.2967A>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018027.5(FRMD4A):​c.2967A>C​(p.Gln989His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: FRMD4A NM_018027.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.92

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11701918).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FRMD4A	NM_018027.5	c.2967A>C	p.Gln989His	missense_variant	Exon 23 of 25	ENST00000357447.7	NP_060497.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FRMD4A	ENST00000357447.7	c.2967A>C	p.Gln989His	missense_variant	Exon 23 of 25	1	NM_018027.5	ENSP00000350032.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 16, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2967A>C (p.Q989H) alteration is located in exon 23 (coding exon 22) of the FRMD4A gene. This alteration results from a A to C substitution at nucleotide position 2967, causing the glutamine (Q) at amino acid position 989 to be replaced by a histidine (H). 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	0.073
BayesDel_addAF	Benign	-0.055	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	17
DANN	Benign	0.84
DEOGEN2	Benign	0.014	T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.75	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.90	N
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	0.41	N
REVEL	Uncertain	0.36
Sift	Benign	0.61	T
Sift4G	Benign	0.57	T
Polyphen		0.0	B
Vest4		0.36
MutPred		0.092		Gain of catalytic residue at Q989 (P = 0.0798);
MVP		0.37
MPC		0.31
ClinPred		0.66	D
GERP RS		3.7
Varity_R		0.11
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs1017080215; hg19: chr10-13696499;