rs886038209

Variant names:

• chrX-12716116-T-C
• rs886038209
• NM_001368397.1:c.1657T>C

Variant summary

Our verdict is Uncertain significance. The variant received 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C553Y) has been classified as Uncertain significance.

• 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
• Publications: 2 publications found

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]

FRMPD4 Gene-Disease associations (from GenCC):

• X-linked complex neurodevelopmental disorder

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• intellectual disability, X-linked 104

  Inheritance: XL Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, Illumina
• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 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 VariationId is 254683.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001368397.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FRMPD4	NM_001368397.1	MANE Select	c.1657T>C	p.Cys553Arg	missense	Exon 15 of 17	NP_001355326.1	A0A6Q8PH73
	FRMPD4	NM_001368395.3		c.1768T>C	p.Cys590Arg	missense	Exon 17 of 19	NP_001355324.1
	FRMPD4	NM_001368396.3		c.1663T>C	p.Cys555Arg	missense	Exon 15 of 17	NP_001355325.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FRMPD4	ENST00000675598.1	MANE Select	c.1657T>C	p.Cys553Arg	missense	Exon 15 of 17	ENSP00000502607.1	A0A6Q8PH73
	FRMPD4	ENST00000380682.5	TSL:1	c.1657T>C	p.Cys553Arg	missense	Exon 15 of 17	ENSP00000370057.1	Q14CM0
	FRMPD4	ENST00000656302.1		c.1711T>C	p.Cys571Arg	missense	Exon 17 of 19	ENSP00000499481.1	A0A590UJL7

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

African (AFR) AF: 0.00 AC: 0 AN: 25710

American (AMR) AF: 0.00 AC: 0 AN: 34160

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18393

East Asian (EAS) AF: 0.00 AC: 0 AN: 28876

South Asian (SAS) AF: 0.00 AC: 0 AN: 52852

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39133

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3982

European-Non Finnish (NFE) AF: 0.00000121 AC: 1 AN: 825520

Other (OTH) AF: 0.00 AC: 0 AN: 44657

GnomAD4 genome Cov.: 21

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	Intellectual disability, X-linked 104 (2)

Computational scores

Source: dbNSFP v4.9

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
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.78	T
M_CAP	Pathogenic	0.36	D
MetaRNN	Uncertain	0.74	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L
PhyloP100		3.6
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.16
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.032	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
Mutation Taster		=42/58	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs886038209; hg19: chrX-12734235;