rs41281644

Positions:

• chr13-101722939-A-G

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_004115.4(FGF14):​c.636T>C​(p.His212His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00157 in 1,613,200 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (4 hom.)
• Consequence: FGF14 NM_004115.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.708

Genes affected

FGF14 (HGNC:3671): (fibroblast growth factor 14) 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. A mutation in this gene is associated with autosomal dominant cerebral ataxia. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jul 2008]

ENSG00000276012 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 13-101722939-A-G is Benign according to our data. Variant chr13-101722939-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 310896.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-101722939-A-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.708 with no splicing effect.
• BS2: High AC in GnomAd4 at 216 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGF14	NM_004115.4	c.636T>C	p.His212His	synonymous_variant	5/5	ENST00000376143.5	NP_004106.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGF14	ENST00000376143.5	c.636T>C	p.His212His	synonymous_variant	5/5	1	NM_004115.4	ENSP00000365313.4

Frequencies

GnomAD3 genomes AF: 0.00142 AC: 216 AN: 151958 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00462

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00216

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00129 AC: 323 AN: 249548 Hom.: 1 AF XY: 0.00133 AC XY: 179 AN XY: 135028

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00319

Gnomad NFE exome AF: 0.00212

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00159 AC: 2324 AN: 1461124 Hom.: 4 Cov.: 31 AF XY: 0.00159 AC XY: 1153 AN XY: 726874

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00350

Gnomad4 NFE exome AF: 0.00184

Gnomad4 OTH exome AF: 0.00103

GnomAD4 genome AF: 0.00142 AC: 216 AN: 152076 Hom.: 0 Cov.: 32 AF XY: 0.00141 AC XY: 105 AN XY: 74330

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.000393

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00462

Gnomad4 NFE AF: 0.00216

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00143 Hom.: 0

Bravo AF: 0.000922

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00142

EpiControl AF: 0.00136

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Spinocerebellar ataxia type 27 Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Jun 28, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 10, 2014	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	FGF14: BP4, BP7, BS1 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 13, 2023	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Dec 08, 2020

- -

FGF14-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 29, 2019

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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	14
DANN	Benign	0.63

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: rs41281644; hg19: chr13-102375289;