rs146951171

Positions:

chr9-105601146-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_001351499.2(FKTN):c.-348G>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000361 in 1,566,964 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0020 ( 3 hom., cov: 32)

Exomes 𝑓: 0.00018 ( 2 hom. )

Consequence

FKTN
NM_001351499.2 5_prime_UTR_premature_start_codon_gain

Scores

Splicing: ADA: 0.004493

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:11

Conservation

PhyloP100: 2.31

Variant links:

Genes affected

FKTN (HGNC:3622): (fukutin) The protein encoded by this gene is a putative transmembrane protein that is localized to the cis-Golgi compartment, where it may be involved in the glycosylation of alpha-dystroglycan in skeletal muscle. The encoded protein is thought to be a glycosyltransferase and could play a role in brain development. Defects in this gene are a cause of Fukuyama-type congenital muscular dystrophy (FCMD), Walker-Warburg syndrome (WWS), limb-girdle muscular dystrophy type 2M (LGMD2M), and dilated cardiomyopathy type 1X (CMD1X). Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Nov 2010]

FKTN links:

FKTN (HGNC:):

FKTN links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008233577).

BP6

Variant 9-105601146-G-A is Benign according to our data. Variant chr9-105601146-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 93518.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Uncertain_significance=3, Benign=1}. Variant chr9-105601146-G-A is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FKTN	NM_001079802.2 linkuse as main transcript	c.167G>A	p.Arg56His	missense_variant, splice_region_variant	5/11	ENST00000357998.10	NP_001073270.1	O75072-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FKTN	ENST00000357998.10 linkuse as main transcript	c.167G>A	p.Arg56His	missense_variant, splice_region_variant	5/11	5	NM_001079802.2	ENSP00000350687.6		O75072-1

Frequencies

GnomAD3 genomes

AF:

0.00203

AC:

308

AN:

152086

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00705

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000590

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:

0.00335

GnomAD3 exomes

AF:

0.000526

AC:

129

AN:

245444

Hom.:

AF XY:

0.000399

AC XY:

AN XY:

132758

show subpopulations

Gnomad AFR exome

AF:

0.00703

Gnomad AMR exome

AF:

0.000410

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000549

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000182

Gnomad OTH exome

AF:

0.000167

GnomAD4 exome

AF:

0.000182

AC:

257

AN:

1414760

Hom.:

Cov.:

AF XY:

0.000163

AC XY:

115

AN XY:

706562

show subpopulations

Gnomad4 AFR exome

AF:

0.00616

Gnomad4 AMR exome

AF:

0.000450

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000508

Gnomad4 SAS exome

AF:

0.0000589

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000654

Gnomad4 OTH exome

AF:

0.000307

GnomAD4 genome

AF:

0.00202

AC:

308

AN:

152204

Hom.:

Cov.:

AF XY:

0.00188

AC XY:

140

AN XY:

74422

show subpopulations

Gnomad4 AFR

AF:

0.00703

Gnomad4 AMR

AF:

0.000589

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:

0.00332

Alfa

AF:

0.000288

Hom.:

Bravo

AF:

0.00193

ESP6500AA

AF:

0.00614

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000667

AC:

Asia WGS

AF:

0.00116

AC:

AN:

3472

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:11

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 03, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 16, 2020	- -

not specified

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 01, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 16, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 26, 2019	Variant summary: FKTN c.167G>A (p.Arg56His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00053 in 245444 control chromosomes, predominantly at a frequency of 0.007 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 1.4 fold the estimated maximal expected allele frequency for a pathogenic variant in FKTN causing Cardiomyopathy phenotype (0.005), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. Co-occurrence with another likely pathogenic variant has been reported (TTN c.34782_34785delTTGT, p.C11595fs*9- internal sample), providing supporting evidence for a benign role. To our knowledge, there are no reports of c.167G>A in individuals affected with Cardiomyopathy and no experimental evidence demonstrating an impact on protein function in the literature. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar (evaluation after 2014) and 5/6 laboratories cited the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -

Walker-Warburg congenital muscular dystrophy

Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 21, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Dilated cardiomyopathy 1X

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

FKTN-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 12, 2019

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

Hypertrophic cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Feb 22, 2017

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 03, 2019

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.20

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.064

T;T;.;.

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.18

FATHMM_MKL

Benign

0.61

LIST_S2

Benign

0.79

.;T;.;T

M_CAP

Benign

0.035

MetaRNN

Benign

0.0082

T;T;T;T

MetaSVM

Benign

-0.32

MutationAssessor

Benign

1.2

L;L;L;L

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.32

.;N;N;N

REVEL

Benign

0.16

Sift

Benign

0.36

.;T;T;T

Sift4G

Benign

0.66

T;T;T;T

Polyphen

0.0060

B;B;.;.

Vest4

0.17

MVP

0.80

MPC

0.10

ClinPred

0.014

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.040

gMVP

0.39

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0045

dbscSNV1_RF

Benign

0.15

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over