chrX-138708889-C-T

Position:

• chrX-138708889-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_004114.5(FGF13):​c.227G>A​(p.Arg76Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000000914 in 1,094,400 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 9.1e-7 (0 hom. 1 hem.)
• Consequence: FGF13 NM_004114.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.85

Genes affected

FGF13 (HGNC:3670): (fibroblast growth factor 13) The protein encoded by this gene is a member of the fibroblast growth factor (FGF) family. FGF family members possess broad mitogenic and cell survival activities, and are involved in a variety of biological processes, including embryonic development, cell growth, morphogenesis, tissue repair, tumor growth, and invasion. This gene is located in a region on chromosome X, which is associated with Borjeson-Forssman-Lehmann syndrome (BFLS), making it a possible candidate gene for familial cases of the BFLS, and for other syndromal and nonspecific forms of X-linked cognitive disability mapping to this region. Alternative splicing of this gene at the 5' end results in several transcript variants encoding different isoforms with different N-termini. [provided by RefSeq, Nov 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.889

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGF13	NM_004114.5	c.227G>A	p.Arg76Gln	missense_variant	2/5	ENST00000315930.11	NP_004105.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGF13	ENST00000315930.11	c.227G>A	p.Arg76Gln	missense_variant	2/5	1	NM_004114.5	ENSP00000322390.6

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 9.14e-7 AC: 1 AN: 1094400 Hom.: 0 Cov.: 28 AF XY: 0.00000278 AC XY: 1 AN XY: 359858

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 24

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jul 10, 2024

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.46
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.74	D;.;.;.;.;D;T
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.78	T;D;D;T;D;T;D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.054	D
MutationAssessor	Benign	1.8	L;.;.;.;.;.;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-2.5	N;D;D;.;N;N;D
REVEL	Pathogenic	0.75
Sift	Benign	0.17	T;T;T;.;T;T;D
Sift4G	Benign	0.23	T;T;T;T;T;.;T
Polyphen		0.97	D;P;.;.;.;.;.
Vest4		0.65
MutPred		0.74		Loss of MoRF binding (P = 0.0203);.;.;.;.;.;.;
MVP		1.0
ClinPred		0.93	D
GERP RS		5.1
Varity_R		0.76
gMVP		0.95

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

Publications

LitVar

Other links and lift over

dbSNP: rs1207647802; hg19: chrX-137791051;