10-13656719-G-A

Variant summary

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

The NM_018027.5(FRMD4A):c.2870C>T(p.Ser957Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000327 in 1,588,544 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000034 (0 hom.)
• Consequence: FRMD4A NM_018027.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.42

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FRMD4A	NM_018027.5	c.2870C>T	p.Ser957Leu	missense_variant	22/25	ENST00000357447.7
FRMD4A	NM_001318337.2	c.2969C>T	p.Ser990Leu	missense_variant	21/24
FRMD4A	NM_001318336.2	c.2918C>T	p.Ser973Leu	missense_variant	21/24
FRMD4A	NM_001318338.2	c.1943C>T	p.Ser648Leu	missense_variant	11/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FRMD4A	ENST00000357447.7	c.2870C>T	p.Ser957Leu	missense_variant	22/25	1	NM_018027.5	P2
FRMD4A	ENST00000495956.3	c.2870C>T	p.Ser957Leu	missense_variant	22/24	2		A2
PRPF18	ENST00000593351.2	n.47+8489G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152216 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000669 AC: 15 AN: 224254 Hom.: 0 AF XY: 0.0000983 AC XY: 12 AN XY: 122110

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000326

Gnomad ASJ exome AF: 0.000428

Gnomad EAS exome AF: 0.0000660

Gnomad SAS exome AF: 0.000256

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000195

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000341 AC: 49 AN: 1436328 Hom.: 0 Cov.: 31 AF XY: 0.0000406 AC XY: 29 AN XY: 714232

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000716

Gnomad4 ASJ exome AF: 0.000471

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000193

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000999

Gnomad4 OTH exome AF: 0.000101

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152216 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74374

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000824 AC: 10

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 03, 2022

The c.2870C>T (p.S957L) 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 2870, causing the serine (S) at amino acid position 957 to be replaced by a leucine (L). 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	Benign	-0.060	T
BayesDel_noAF	Uncertain	-0.030
Cadd	Pathogenic	31
Dann	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.23	D
MetaRNN	Uncertain	0.51	D
MetaSVM	Uncertain	0.58	D
MutationAssessor	Uncertain	2.1	M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.49
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.014	D
Polyphen		0.99	D
Vest4		0.66
MutPred		0.23		Loss of phosphorylation at S957 (P = 0.004);
MVP		0.54
MPC		1.0
ClinPred		0.30	T
GERP RS		4.7
Varity_R		0.49
gMVP		0.42

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: rs143274194; hg19: chr10-13698719; COSMIC: COSV100662368; COSMIC: COSV100662368;