X-12609800-G-A

Variant summary

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

The NM_001368397.1(FRMPD4):c.238G>A(p.Glu80Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000182 in 1,096,505 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000018 (0 hom. 1 hem.)
• Consequence: FRMPD4 NM_001368397.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.55

Genes affected

FRMPD4 (HGNC:29007): (FERM and PDZ domain containing 4) This gene encodes a multi-domain (WW, PDZ, FERM) containing protein. Through its interaction with other proteins (such as PSD-95), it functions as a positive regulator of dendritic spine morphogenesis and density, and is required for the maintenance of excitatory synaptic transmission. [provided by RefSeq, Jan 2010]

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
FRMPD4	NM_001368397.1	c.238G>A	p.Glu80Lys	missense_variant	3/17	ENST00000675598.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FRMPD4	ENST00000675598.1	c.238G>A	p.Glu80Lys	missense_variant	3/17		NM_001368397.1	P2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000182 AC: 2 AN: 1096505 Hom.: 0 Cov.: 29 AF XY: 0.00000276 AC XY: 1 AN XY: 361877

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: 0.00000238

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 03, 2020

The c.238G>A (p.E80K) alteration is located in coding exon 3 of the FRMPD4 gene. This alteration results from a G to A substitution at nucleotide position 238, causing the glutamic acid (E) at amino acid position 80 to be replaced by a lysine (K). The alteration is not observed in healthy cohorts:_x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the FRMPD4 c.238G>A alteration was not observed, with coverage at this site. The altered amino acid is conserved throughout evolution:_x000D_ _x000D_ The p.E80 amino acid is conserved in available vertebrate species. The amino acid is located in a functionally important protein domain:_x000D_ _x000D_ The p.E80K amino acid is located in the PDZ domain which forms a peptide-binding groove for protein-protein interactions including PSD95. The PDZ domain is required for the positive regulation of dendritic spine density in neurons (Lee, 2008). The alteration is predicted benign by in silico models:_x000D_ _x000D_ The p.E80K alteration is predicted to be benign by Polyphen and tolerated by SIFT in silico analyses. 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	Pathogenic	0.64
BayesDel_addAF	Benign	-0.014	T
BayesDel_noAF	Benign	-0.26
Cadd	Uncertain	25
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.041	T;T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Uncertain	0.45	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.99	L;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-1.1	N;.
REVEL	Benign	0.23
Sift	Benign	0.056	T;.
Sift4G	Benign	0.56	T;T
Polyphen		0.21	B;.
Vest4		0.60
MutPred		0.57		Gain of catalytic residue at E80 (P = 0.0065);.;
MVP		0.73
MPC		2.1
ClinPred		0.94	D
GERP RS		5.1
Varity_R		0.62
gMVP		0.74

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: rs2059163980; hg19: chrX-12627919;