chr13-101721219-C-A

Variant names:

• chr13-101721219-C-A
• rs1046197
• NM_004115.4:c.*1612G>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_004115.4(FGF14):​c.*1612G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.296 in 151,820 control chromosomes in the GnomAD database, including 7,311 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (7311 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: FGF14 NM_004115.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.10
• Publications: 3 publications found

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]

FGF14 Gene-Disease associations (from GenCC):

• spinocerebellar ataxia 27A

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• spinocerebellar ataxia type 27

  Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet
• autosomal recessive cerebellar ataxia

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000276012 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 13-101721219-C-A is Benign according to our data. Variant chr13-101721219-C-A is described in ClinVar as [Benign]. Clinvar id is 310865.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.477 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGF14	NM_004115.4	c.*1612G>T		3_prime_UTR_variant	Exon 5 of 5	ENST00000376143.5	NP_004106.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGF14	ENST00000376143.5	c.*1612G>T		3_prime_UTR_variant	Exon 5 of 5	1	NM_004115.4	ENSP00000365313.4

Frequencies

GnomAD3 genomes AF: 0.297 AC: 44980 AN: 151702 Hom.: 7306 Cov.: 32

Gnomad AFR AF: 0.168

Gnomad AMI AF: 0.359

Gnomad AMR AF: 0.292

Gnomad ASJ AF: 0.332

Gnomad EAS AF: 0.493

Gnomad SAS AF: 0.432

Gnomad FIN AF: 0.295

Gnomad MID AF: 0.405

Gnomad NFE AF: 0.347

Gnomad OTH AF: 0.322

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.296 AC: 44997 AN: 151820 Hom.: 7311 Cov.: 32 AF XY: 0.295 AC XY: 21884 AN XY: 74188

African (AFR) AF: 0.168 AC: 6952 AN: 41412

American (AMR) AF: 0.292 AC: 4444 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.332 AC: 1151 AN: 3470

East Asian (EAS) AF: 0.493 AC: 2535 AN: 5140

South Asian (SAS) AF: 0.431 AC: 2080 AN: 4822

European-Finnish (FIN) AF: 0.295 AC: 3111 AN: 10560

Middle Eastern (MID) AF: 0.405 AC: 119 AN: 294

European-Non Finnish (NFE) AF: 0.347 AC: 23581 AN: 67872

Other (OTH) AF: 0.331 AC: 697 AN: 2108

Alfa AF: 0.307 Hom.: 941

Bravo AF: 0.291

Asia WGS AF: 0.479 AC: 1666 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Spinocerebellar ataxia type 27 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	12
DANN	Benign	0.76
PhyloP100		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1046197; hg19: chr13-102373569;