X-12718765-G-A

Variant names:

• chrX-12718765-G-A
• NM_001368397.1:c.3939G>A
• FRMPD4 p.Arg1313Arg

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP7 BS2

The NM_001368397.1(FRMPD4):​c.3939G>A​(p.Arg1313Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000101 in 1,085,813 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. R1313R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.000010 (0 hom. 3 hem.)
• Consequence: FRMPD4 NM_001368397.1 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.989
• 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: G2P, Ambry Genetics, Illumina, Labcorp Genetics (formerly Invitae)
• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP7: Synonymous conserved (PhyloP=0.989 with no splicing effect.
• BS2: High Hemizygotes in GnomAdExome4 at 3 XL gene

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.3939G>A	p.Arg1313Arg	synonymous	Exon 16 of 17	NP_001355326.1	A0A6Q8PH73
	FRMPD4	NM_001368395.3		c.4050G>A	p.Arg1350Arg	synonymous	Exon 18 of 19	NP_001355324.1
	FRMPD4	NM_001368396.3		c.3945G>A	p.Arg1315Arg	synonymous	Exon 16 of 17	NP_001355325.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FRMPD4	ENST00000675598.1	MANE Select	c.3939G>A	p.Arg1313Arg	synonymous	Exon 16 of 17	ENSP00000502607.1	A0A6Q8PH73
	FRMPD4	ENST00000380682.5	TSL:1	c.3939G>A	p.Arg1313Arg	synonymous	Exon 16 of 17	ENSP00000370057.1	Q14CM0
	FRMPD4	ENST00000656302.1		c.3993G>A	p.Arg1331Arg	synonymous	Exon 18 of 19	ENSP00000499481.1	A0A590UJL7

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.0000101 AC: 11 AN: 1085813 Hom.: 0 Cov.: 29 AF XY: 0.00000853 AC XY: 3 AN XY: 351859

African (AFR) AF: 0.00 AC: 0 AN: 26199

American (AMR) AF: 0.00 AC: 0 AN: 35113

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19276

East Asian (EAS) AF: 0.00 AC: 0 AN: 30143

South Asian (SAS) AF: 0.00 AC: 0 AN: 53684

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40235

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4103

European-Non Finnish (NFE) AF: 0.0000132 AC: 11 AN: 831391

Other (OTH) AF: 0.00 AC: 0 AN: 45669

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	3.6
DANN	Benign	0.61
PhyloP100		0.99

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chrX-12736884;