9-105604242-A-T

Position:

• chr9-105604242-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_001079802.2(FKTN):​c.397A>T​(p.Met133Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FKTN NM_001079802.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.67

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a mutagenesis_site Decrease in ribitol-5-phosphate transferase activity. (size 0) in uniprot entity FKTN_HUMAN
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FKTN	NM_001079802.2	c.397A>T	p.Met133Leu	missense_variant	6/11	ENST00000357998.10	NP_001073270.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FKTN	ENST00000357998.10	c.397A>T	p.Met133Leu	missense_variant	6/11	5	NM_001079802.2	ENSP00000350687.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 27, 2022

The p.M133L variant (also known as c.397A>T), located in coding exon 4 of the FKTN gene, results from an A to T substitution at nucleotide position 397. The methionine at codon 133 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.098	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	18
DANN	Benign	0.96
DEOGEN2	Benign	0.18	T;T;.;.
Eigen	Benign	-0.0065
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.84	.;T;.;T
M_CAP	Benign	0.052	D
MetaRNN	Uncertain	0.46	T;T;T;T
MetaSVM	Uncertain	0.16	D
MutationAssessor	Benign	2.0	M;M;M;M
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.94	.;N;N;N
REVEL	Uncertain	0.32
Sift	Benign	0.38	.;T;T;T
Sift4G	Benign	0.39	T;T;T;T
Polyphen		0.042	B;B;.;.
Vest4		0.59
MutPred		0.45		Gain of helix (P = 0.0854);Gain of helix (P = 0.0854);Gain of helix (P = 0.0854);Gain of helix (P = 0.0854);
MVP		0.61
MPC		0.079
ClinPred		0.55	D
GERP RS		5.1
Varity_R		0.30
gMVP		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs569778463; hg19: chr9-108366523;