X-138635469-T-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4 BP6_Very_Strong BS2

The NM_004114.5(FGF13):c.589A>C(p.Lys197Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000413 in 1,209,212 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 13 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., 7 hem., cov: 24)
  • Exomes 𝑓: 0.000021 (0 hom. 6 hem.)
• Consequence: FGF13 NM_004114.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 7.67

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3360319).
• BP6: Variant X-138635469-T-G is Benign according to our data. Variant chrX-138635469-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 2661530.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAd at 7 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FGF13	NM_004114.5	c.589A>C	p.Lys197Gln	missense_variant	4/5	ENST00000315930.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGF13	ENST00000315930.11	c.589A>C	p.Lys197Gln	missense_variant	4/5	1	NM_004114.5	P4

Frequencies

GnomAD3 genomes AF: 0.000241 AC: 27 AN: 111993 Hom.: 0 Cov.: 24 AF XY: 0.000205 AC XY: 7 AN XY: 34147

Gnomad AFR AF: 0.000649

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000668

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000436 AC: 8 AN: 183464 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 67908

Gnomad AFR exome AF: 0.000532

Gnomad AMR exome AF: 0.0000365

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000210 AC: 23 AN: 1097219 Hom.: 0 Cov.: 30 AF XY: 0.0000165 AC XY: 6 AN XY: 362601

Gnomad4 AFR exome AF: 0.000758

Gnomad4 AMR exome AF: 0.0000568

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: 0.00

Gnomad4 OTH exome AF: 0.0000217

GnomAD4 genome AF: 0.000241 AC: 27 AN: 111993 Hom.: 0 Cov.: 24 AF XY: 0.000205 AC XY: 7 AN XY: 34147

Gnomad4 AFR AF: 0.000649

Gnomad4 AMR AF: 0.000668

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000483 Hom.: 2

Bravo AF: 0.000242

ESP6500AA AF: 0.000782 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000494 AC: 6

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

FGF13-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 20, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Dec 01, 2022

FGF13: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	0.0
Cadd	Pathogenic	26
Dann	Uncertain	0.99
DEOGEN2	Benign	0.36	T;.;.;.;.
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.34	T;T;T;T;T
MetaSVM	Benign	-0.62	T
MutationAssessor	Uncertain	2.4	M;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-2.0	N;N;N;.;N
REVEL	Benign	0.24
Sift	Benign	0.080	T;T;T;.;D
Sift4G	Benign	0.096	T;T;T;T;T
Polyphen		0.65	P;P;.;.;.
Vest4		0.71
MVP		0.91
ClinPred		0.10	T
GERP RS		6.2
Varity_R		0.91
gMVP		0.83

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: rs17510270; hg19: chrX-137717630;