rs886038209

Positions:

• chrX-12716116-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_001368397.1(FRMPD4):​c.1657T>C​(p.Cys553Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000932 in 1,073,283 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 9.3e-7 (0 hom. 1 hem.)
• Consequence: FRMPD4 NM_001368397.1 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 3.62

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-12716116-T-C is Pathogenic according to our data. Variant chrX-12716116-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 254683.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-12716116-T-C is described in Lovd as [Pathogenic]. Variant chrX-12716116-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FRMPD4	NM_001368397.1	c.1657T>C	p.Cys553Arg	missense_variant	15/17	ENST00000675598.1	NP_001355326.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FRMPD4	ENST00000675598.1	c.1657T>C	p.Cys553Arg	missense_variant	15/17		NM_001368397.1	ENSP00000502607	P2

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome AF: 9.32e-7 AC: 1 AN: 1073283 Hom.: 0 Cov.: 30 AF XY: 0.00000288 AC XY: 1 AN XY: 347057

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: 0.00000121

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 21

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual disability, X-linked 104 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 20, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 13, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.0022	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.070	T;T
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.78	T;T
M_CAP	Pathogenic	0.36	D
MetaRNN	Uncertain	0.74	D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.6	N;.
REVEL	Benign	0.16
Sift	Pathogenic	0.0	D;.
Sift4G	Uncertain	0.032	D;D
Polyphen		0.88	P;.
Vest4		0.85
MutPred		0.43		Gain of disorder (P = 0.0415);.;
MVP		0.44
MPC		0.52
ClinPred		0.93	D
GERP RS		5.5
Varity_R		0.97
gMVP		0.81

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: rs886038209; hg19: chrX-12734235;