X-12718763-C-A

Variant names:

• chrX-12718763-C-A
• rs41303149
• NM_001368397.1:c.3937C>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Moderate BP6 BP7 BS2

The NM_001368397.1(FRMPD4):​c.3937C>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 0.00191 in 1,198,771 control chromosomes in the GnomAD database, including 8 homozygotes. There are 742 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., 46 hem., cov: 23)
  • Exomes 𝑓: 0.0020 (8 hom. 696 hem.)
• Consequence: FRMPD4 NM_001368397.1 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 2.60
• Publications: 1 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.24).
• BP6: Variant X-12718763-C-A is Benign according to our data. Variant chrX-12718763-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 167103.
• BP7: Synonymous conserved (PhyloP=2.6 with no splicing effect.
• BS2: High Hemizygotes in GnomAd4 at 46 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.3937C>A	p.Arg1313Arg	synonymous	Exon 16 of 17	NP_001355326.1	A0A6Q8PH73
	FRMPD4	NM_001368395.3		c.4048C>A	p.Arg1350Arg	synonymous	Exon 18 of 19	NP_001355324.1
	FRMPD4	NM_001368396.3		c.3943C>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.3937C>A	p.Arg1313Arg	synonymous	Exon 16 of 17	ENSP00000502607.1	A0A6Q8PH73
	FRMPD4	ENST00000380682.5	TSL:1	c.3937C>A	p.Arg1313Arg	synonymous	Exon 16 of 17	ENSP00000370057.1	Q14CM0
	FRMPD4	ENST00000656302.1		c.3991C>A	p.Arg1331Arg	synonymous	Exon 18 of 19	ENSP00000499481.1	A0A590UJL7

Frequencies

GnomAD3 genomes AF: 0.00147 AC: 165 AN: 111968 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.000227

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000941

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00447

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00244

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00184 AC: 330 AN: 179217 AF XY: 0.00176

Gnomad AFR exome AF: 0.000156

Gnomad AMR exome AF: 0.000184

Gnomad ASJ exome AF: 0.000137

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00526

Gnomad NFE exome AF: 0.00263

Gnomad OTH exome AF: 0.00225

GnomAD4 exome AF: 0.00195 AC: 2123 AN: 1086750 Hom.: 8 Cov.: 29 AF XY: 0.00197 AC XY: 696 AN XY: 352788

African (AFR) AF: 0.000153 AC: 4 AN: 26213

American (AMR) AF: 0.000199 AC: 7 AN: 35108

Ashkenazi Jewish (ASJ) AF: 0.000207 AC: 4 AN: 19280

East Asian (EAS) AF: 0.0000332 AC: 1 AN: 30148

South Asian (SAS) AF: 0.00101 AC: 54 AN: 53701

European-Finnish (FIN) AF: 0.00430 AC: 173 AN: 40238

Middle Eastern (MID) AF: 0.000244 AC: 1 AN: 4106

European-Non Finnish (NFE) AF: 0.00216 AC: 1795 AN: 832253

Other (OTH) AF: 0.00184 AC: 84 AN: 45703

GnomAD4 genome AF: 0.00147 AC: 165 AN: 112021 Hom.: 0 Cov.: 23 AF XY: 0.00134 AC XY: 46 AN XY: 34203

African (AFR) AF: 0.000227 AC: 7 AN: 30865

American (AMR) AF: 0.0000939 AC: 1 AN: 10644

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2645

East Asian (EAS) AF: 0.00 AC: 0 AN: 3560

South Asian (SAS) AF: 0.00 AC: 0 AN: 2629

European-Finnish (FIN) AF: 0.00447 AC: 27 AN: 6041

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.00244 AC: 130 AN: 53204

Other (OTH) AF: 0.00 AC: 0 AN: 1531

Alfa AF: 0.00180 Hom.: 26

Bravo AF: 0.00126

EpiCase AF: 0.00175

EpiControl AF: 0.00166

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	1	Autism, susceptibility to, X-linked 4 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.24
CADD	Benign	9.7
DANN	Benign	0.69
PhyloP100		2.6
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs41303149; hg19: chrX-12736882;