Genetic Variant ENST00000376131.9:c.142A>T (chr13-102401537-T-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The ENST00000376131.9(FGF14):c.142A>T(p.Ser48Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000142 in 1,614,068 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

FGF14
ENST00000376131.9 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.46

Publications

0 publications found

Variant links:

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: Orphanet, Ambry Genetics
autosomal recessive cerebellar ataxia
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

FGF14 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.828

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000376131.9. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	HGVSc	Effect	Exon Rank	Protein
FGF14	NM_001321938.2	c.-291A>T	5_prime_UTR_premature_start_codon_gain	Exon 2 of 7	NP_001308867.1
FGF14	NM_001321940.1	c.-291A>T	5_prime_UTR_premature_start_codon_gain	Exon 1 of 6	NP_001308869.1
FGF14	NM_001321941.2	c.-127A>T	5_prime_UTR_premature_start_codon_gain	Exon 1 of 6	NP_001308870.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FGF14	ENST00000376131.9	TSL:1	c.142A>T	p.Ser48Cys	missense	Exon 1 of 5	ENSP00000365301.3	Q92915-2
FGF14	ENST00000418923.3	TSL:3	c.25A>T	p.Ser9Cys	missense	Exon 2 of 6	ENSP00000516414.1	A0A9L9PXK7
FGF14	ENST00000706494.1		c.-293-2A>T		splice_acceptor intron	N/A	ENSP00000516417.1	A0A9L9PX77

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000159

AC:

AN:

251460

AF XY:

0.0000221

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000150

AC:

AN:

1461884

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.0000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000189

AC:

AN:

1112008

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74344

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41434

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.00000378

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Uncertain

0.053

BayesDel_noAF

Uncertain

-0.080

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.75

M_CAP

Uncertain

0.23

MetaRNN

Pathogenic

0.83

MetaSVM

Uncertain

0.41

PhyloP100

7.5

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-1.7

REVEL

Uncertain

0.53

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0040

Polyphen

1.0

Vest4

0.74

MutPred

0.49

Gain of catalytic residue at G50 (P = 0.0018)

MVP

0.50

MPC

1.4

ClinPred

0.94

GERP RS

4.7

PromoterAI

-0.064

Neutral

(source)

gMVP

0.71

Mutation Taster

=49/51

disease causing

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over