rs759503727

Variant names:

• chrX-12718764-G-A
• rs759503727
• NM_001368397.1:c.3938G>A

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The ENST00000675598.1(FRMPD4):​c.3938G>A​(p.Arg1313Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000576 in 1,197,884 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 32 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R1313R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000045 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.000059 (0 hom. 32 hem.)
• Consequence: FRMPD4 ENST00000675598.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 6.44
• Publications: 0 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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Illumina
• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14297307).
• BP6: Variant X-12718764-G-A is Benign according to our data. Variant chrX-12718764-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 211054.
• BS2: High Hemizygotes in GnomAdExome4 at 32 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000675598.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FRMPD4	NM_001368397.1	MANE Select	c.3938G>A	p.Arg1313Gln	missense	Exon 16 of 17	NP_001355326.1
	FRMPD4	NM_001368395.3		c.4049G>A	p.Arg1350Gln	missense	Exon 18 of 19	NP_001355324.1
	FRMPD4	NM_001368396.3		c.3944G>A	p.Arg1315Gln	missense	Exon 16 of 17	NP_001355325.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FRMPD4	ENST00000675598.1	MANE Select	c.3938G>A	p.Arg1313Gln	missense	Exon 16 of 17	ENSP00000502607.1
	FRMPD4	ENST00000380682.5	TSL:1	c.3938G>A	p.Arg1313Gln	missense	Exon 16 of 17	ENSP00000370057.1
	FRMPD4	ENST00000656302.1		c.3992G>A	p.Arg1331Gln	missense	Exon 18 of 19	ENSP00000499481.1

Frequencies

GnomAD3 genomes AF: 0.0000447 AC: 5 AN: 111885 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000378

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000382

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000564

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000140 AC: 25 AN: 179092 AF XY: 0.000183

Gnomad AFR exome AF: 0.0000779

Gnomad AMR exome AF: 0.0000369

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000626

Gnomad NFE exome AF: 0.000152

Gnomad OTH exome AF: 0.000226

GnomAD4 exome AF: 0.0000589 AC: 64 AN: 1085999 Hom.: 0 Cov.: 29 AF XY: 0.0000909 AC XY: 32 AN XY: 351965

African (AFR) AF: 0.0000382 AC: 1 AN: 26200

American (AMR) AF: 0.0000285 AC: 1 AN: 35115

Ashkenazi Jewish (ASJ) AF: 0.000156 AC: 3 AN: 19278

East Asian (EAS) AF: 0.00 AC: 0 AN: 30148

South Asian (SAS) AF: 0.000410 AC: 22 AN: 53673

European-Finnish (FIN) AF: 0.0000746 AC: 3 AN: 40236

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4104

European-Non Finnish (NFE) AF: 0.0000373 AC: 31 AN: 831584

Other (OTH) AF: 0.0000657 AC: 3 AN: 45661

GnomAD4 genome AF: 0.0000447 AC: 5 AN: 111885 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34077

African (AFR) AF: 0.00 AC: 0 AN: 30769

American (AMR) AF: 0.00 AC: 0 AN: 10601

Ashkenazi Jewish (ASJ) AF: 0.000378 AC: 1 AN: 2647

East Asian (EAS) AF: 0.00 AC: 0 AN: 3567

South Asian (SAS) AF: 0.000382 AC: 1 AN: 2621

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6044

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 237

European-Non Finnish (NFE) AF: 0.0000564 AC: 3 AN: 53206

Other (OTH) AF: 0.00 AC: 0 AN: 1507

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000416

ExAC AF: 0.000198 AC: 24

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Inborn genetic diseases (1)
-	-	1	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.037	T
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.63	N
PhyloP100		6.4
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.30	N
REVEL	Benign	0.28
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.022	D
Polyphen		0.47	P
Vest4		0.33
MutPred		0.42		Gain of ubiquitination at K1318 (P = 0.0261)
MVP		0.62
MPC		0.16
ClinPred		0.073	T
GERP RS		4.7
Varity_R		0.63
gMVP		0.53
Mutation Taster		=96/4	polymorphism

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: rs759503727; hg19: chrX-12736883; COSMIC: COSV107482647;