chr13-101721213-A-T

Variant names:

• chr13-101721213-A-T
• rs15608
• NM_004115.4:c.*1618T>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004115.4(FGF14):​c.*1618T>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.771 in 151,992 control chromosomes in the GnomAD database, including 45,343 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.77 (45343 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: -0.593
• Publications: 4 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 13-101721213-A-T is Benign according to our data. Variant chr13-101721213-A-T is described in ClinVar as [Benign]. Clinvar id is 310863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.933 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGF14	NM_004115.4	c.*1618T>A		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.*1618T>A		3_prime_UTR_variant	Exon 5 of 5	1	NM_004115.4	ENSP00000365313.4

Frequencies

GnomAD3 genomes AF: 0.771 AC: 117085 AN: 151874 Hom.: 45303 Cov.: 32

Gnomad AFR AF: 0.765

Gnomad AMI AF: 0.722

Gnomad AMR AF: 0.836

Gnomad ASJ AF: 0.792

Gnomad EAS AF: 0.956

Gnomad SAS AF: 0.812

Gnomad FIN AF: 0.781

Gnomad MID AF: 0.801

Gnomad NFE AF: 0.741

Gnomad OTH AF: 0.774

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: 0.771 AC: 117177 AN: 151992 Hom.: 45343 Cov.: 32 AF XY: 0.774 AC XY: 57517 AN XY: 74272

African (AFR) AF: 0.765 AC: 31737 AN: 41484

American (AMR) AF: 0.836 AC: 12753 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.792 AC: 2746 AN: 3466

East Asian (EAS) AF: 0.955 AC: 4911 AN: 5140

South Asian (SAS) AF: 0.812 AC: 3917 AN: 4822

European-Finnish (FIN) AF: 0.781 AC: 8254 AN: 10566

Middle Eastern (MID) AF: 0.799 AC: 235 AN: 294

European-Non Finnish (NFE) AF: 0.741 AC: 50331 AN: 67956

Other (OTH) AF: 0.776 AC: 1636 AN: 2108

Alfa AF: 0.650 Hom.: 1777

Bravo AF: 0.780

Asia WGS AF: 0.903 AC: 3138 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	-0.62
CADD	Benign	0.28
DANN	Benign	0.80
PhyloP100		-0.59
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: rs15608; hg19: chr13-102373563;