rs41303149

chrX-12718763-C-AchrX-12718763-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Moderate BP6 BP7 BS2

The NM_001368397.1(FRMPD4):c.3937C>A(p.Arg1313=) 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

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 Benign. Variant got -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 id is 167103.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1, Likely_benign=2}. Variant chrX-12718763-C-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=2.6 with no splicing effect.
• BS2: High Hemizygotes in GnomAd at 46 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FRMPD4	NM_001368397.1	c.3937C>A	p.Arg1313=	synonymous_variant	16/17	ENST00000675598.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FRMPD4	ENST00000675598.1	c.3937C>A	p.Arg1313=	synonymous_variant	16/17		NM_001368397.1	P2

Frequencies

GnomAD3 genomes AF: 0.00147 AC: 165 AN: 111968 Hom.: 0 Cov.: 23 AF XY: 0.00135 AC XY: 46 AN XY: 34140

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

GnomAD3 exomes AF: 0.00184 AC: 330 AN: 179217 Hom.: 0 AF XY: 0.00176 AC XY: 115 AN XY: 65499

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 SAS exome AF: 0.00107

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

Gnomad4 AFR exome AF: 0.000153

Gnomad4 AMR exome AF: 0.000199

Gnomad4 ASJ exome AF: 0.000207

Gnomad4 EAS exome AF: 0.0000332

Gnomad4 SAS exome AF: 0.00101

Gnomad4 FIN exome AF: 0.00430

Gnomad4 NFE exome AF: 0.00216

Gnomad4 OTH exome AF: 0.00184

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

Gnomad4 AFR AF: 0.000227

Gnomad4 AMR AF: 0.0000939

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00447

Gnomad4 NFE AF: 0.00244

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00188 Hom.: 26

Bravo AF: 0.00126

EpiCase AF: 0.00175

EpiControl AF: 0.00166

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 20, 2014	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Oct 29, 2015

- -

Autism, susceptibility to, X-linked 4 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Nov 01, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.24
Cadd	Benign	9.7
Dann	Benign	0.69

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

Publications

LitVar

Other links and lift over

dbSNP: rs41303149; hg19: chrX-12736882;