rs193922689

Positions:

chr9-105601141-A-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP3BP6BS2

The NM_001079802.2(FKTN):c.166-4A>G variant causes a splice region, splice polypyrimidine tract, intron change. The variant allele was found at a frequency of 0.00084 in 1,553,096 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0012 ( 2 hom., cov: 33)

Exomes 𝑓: 0.00080 ( 2 hom. )

Consequence

FKTN
NM_001079802.2 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.9986

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9B:3

Conservation

PhyloP100: 3.96

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

BP6

Variant 9-105601141-A-G is Benign according to our data. Variant chr9-105601141-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 36139.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=9, Benign=1, Likely_benign=2}.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FKTN	NM_001079802.2 linkuse as main transcript	c.166-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000357998.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FKTN	ENST00000357998.10 linkuse as main transcript	c.166-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_001079802.2	P1	O75072-1

Frequencies

GnomAD3 genomes

AF:

0.00119

AC:

181

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00480

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00173

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.000761

AC:

185

AN:

243196

Hom.:

AF XY:

0.000851

AC XY:

112

AN XY:

131634

show subpopulations

Gnomad AFR exome

AF:

0.000128

Gnomad AMR exome

AF:

0.0000588

Gnomad ASJ exome

AF:

0.000607

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00297

Gnomad NFE exome

AF:

0.00101

Gnomad OTH exome

AF:

0.000336

GnomAD4 exome

AF:

0.000802

AC:

1124

AN:

1400782

Hom.:

Cov.:

AF XY:

0.000873

AC XY:

611

AN XY:

700228

show subpopulations

Gnomad4 AFR exome

AF:

0.0000619

Gnomad4 AMR exome

AF:

0.0000677

Gnomad4 ASJ exome

AF:

0.000703

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00291

Gnomad4 NFE exome

AF:

0.000850

Gnomad4 OTH exome

AF:

0.000791

GnomAD4 genome

AF:

0.00119

AC:

181

AN:

152314

Hom.:

Cov.:

AF XY:

0.00133

AC XY:

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.000865

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00480

Gnomad4 NFE

AF:

0.00174

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00156

Hom.:

Bravo

AF:

0.000552

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 22, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 03, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 17, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 20, 2021	This variant is associated with the following publications: (PMID: 28798025) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2019	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Feb 28, 2022

Variant summary: FKTN c.166-4A>G alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 3 prime acceptor site; one predict the variant weakens a 3 prime acceptor site; three predict the variant creates a 3 prime acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00076 in 243196 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in FKTN causing Cardiomyopathy (0.00076 vs 0.005), allowing no conclusion about variant significance. c.166-4A>G has been reported in the literature in individuals affected with Cardiomyopathy. This report does not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (Benign/likely benign n=2, VUS n=5). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Myopathy caused by variation in FKTN

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Oct 19, 2020

Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as 3C-VUS. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with muscular dystrophy-dystroglycanopathy type A (MIM#253800), type B (MIM#613152), type C (MIM#611588), and dilated cardiomyopathy (MIM#611615) (OMIM). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0212 - Non-canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (260 heterozygotes, 2 homozygotes). (SP) 0508 - In silico predictions for abnormal splicing are conflicting. (I) 0705 - No comparable non-canonical splice variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. The variant has one benign and five VUS entries in ClinVar. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Dilated cardiomyopathy 1X

Uncertain:1

Uncertain significance, 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, 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. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 02, 2022

The c.166-4A>G intronic alteration consists of a A to G substitution 4 nucleotides before coding exon 3 in the FKTN gene. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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 13, 2018

FKTN-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 30, 2023

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). -

Walker-Warburg congenital muscular dystrophy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.26

CADD

Uncertain

DANN

Benign

0.96

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.81

SpliceAI score (max)

0.85

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.85

Position offset: 1

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