10-13656707-G-A

Variant names:

• chr10-13656707-G-A
• rs1296396351
• NM_018027.5:c.2882C>T

Variant summary

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

The NM_018027.5(FRMD4A):​c.2882C>T​(p.Thr961Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000758 in 1,583,870 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: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000077 (0 hom.)
• Consequence: FRMD4A NM_018027.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.12

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=0.18898955).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FRMD4A	NM_018027.5	c.2882C>T	p.Thr961Ile	missense_variant	Exon 22 of 25	ENST00000357447.7	NP_060497.3
FRMD4A	NM_001318337.2	c.2981C>T	p.Thr994Ile	missense_variant	Exon 21 of 24		NP_001305266.1
FRMD4A	NM_001318336.2	c.2930C>T	p.Thr977Ile	missense_variant	Exon 21 of 24		NP_001305265.1
FRMD4A	NM_001318338.2	c.1955C>T	p.Thr652Ile	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.2882C>T	p.Thr961Ile	missense_variant	Exon 22 of 25	1	NM_018027.5	ENSP00000350032.2
FRMD4A	ENST00000495956.3	c.2882C>T	p.Thr961Ile	missense_variant	Exon 22 of 24	2		ENSP00000488764.2
PRPF18	ENST00000593351.2	n.47+8477G>A		intron_variant	Intron 1 of 2	5

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152208 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000768 AC: 11 AN: 1431662 Hom.: 0 Cov.: 31 AF XY: 0.00000562 AC XY: 4 AN XY: 711844

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000100

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152208 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74360

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 15, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2882C>T (p.T961I) 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 2882, causing the threonine (T) at amino acid position 961 to be replaced by an isoleucine (I). 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	0.13
BayesDel_addAF	Uncertain	0.042	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.018	T
Eigen	Benign	-0.11
Eigen_PC	Benign	0.077
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.074	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	1.2	L
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.66	N
REVEL	Uncertain	0.31
Sift	Benign	0.26	T
Sift4G	Benign	0.19	T
Polyphen		0.037	B
Vest4		0.51
MutPred		0.22		Gain of sheet (P = 0.0101);
MVP		0.20
MPC		0.38
ClinPred		0.72	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.18
gMVP		0.27

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: rs1296396351; hg19: chr10-13698707;