rs1557194488

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3PP5

The NM_000116.5(TAFAZZIN):​c.790A>G​(p.Lys264Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 22)

Consequence

TAFAZZIN
NM_000116.5 missense

Scores

8
7
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2

Conservation

PhyloP100: 8.20
Variant links:
Genes affected
TAFAZZIN (HGNC:11577): (tafazzin, phospholipid-lysophospholipid transacylase) This gene encodes a protein that is expressed at high levels in cardiac and skeletal muscle. Mutations in this gene have been associated with a number of clinical disorders including Barth syndrome, dilated cardiomyopathy (DCM), hypertrophic DCM, endocardial fibroelastosis, and left ventricular noncompaction (LVNC). Multiple transcript variants encoding different isoforms have been described. A long form and a short form of each of these isoforms is produced; the short form lacks a hydrophobic leader sequence and may exist as a cytoplasmic protein rather than being membrane-bound. Other alternatively spliced transcripts have been described but the full-length nature of all these transcripts is not known. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.786
PP5
Variant X-154420915-A-G is Pathogenic according to our data. Variant chrX-154420915-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 430910.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TAFAZZINNM_000116.5 linkc.790A>G p.Lys264Glu missense_variant 11/11 ENST00000601016.6 NP_000107.1 Q16635-1A0A0S2Z4K0

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TAFAZZINENST00000601016.6 linkc.790A>G p.Lys264Glu missense_variant 11/111 NM_000116.5 ENSP00000469981.1 Q16635-1

Frequencies

GnomAD3 genomes
Cov.:
22
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
22

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

3-Methylglutaconic aciduria type 2 Pathogenic:1Uncertain:1
Likely pathogenic, criteria provided, single submitterclinical testingDepartment of Immunology, University Hospital Southampton NHSFT-- -
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 03, 2022This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 264 of the TAZ protein (p.Lys264Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Barth syndrome (PMID: 29077208). This variant is also known as c.658A>G; p.Lys220Glu. ClinVar contains an entry for this variant (Variation ID: 430910). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxSep 13, 2017The K264E variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The K264E variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The K264E variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.88
BayesDel_addAF
Pathogenic
0.41
D
BayesDel_noAF
Pathogenic
0.35
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Benign
0.40
.;.;.;T;.
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.94
D;D;D;D;D
M_CAP
Pathogenic
0.97
D
MetaRNN
Pathogenic
0.79
D;D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Uncertain
2.7
.;.;.;M;.
PrimateAI
Uncertain
0.67
T
PROVEAN
Uncertain
-3.6
.;.;.;.;D
REVEL
Pathogenic
0.77
Sift
Uncertain
0.0010
.;.;.;.;D
Sift4G
Uncertain
0.023
D;D;D;D;T
Polyphen
1.0
D;D;D;D;.
Vest4
0.64
MutPred
0.46
.;.;.;Loss of ubiquitination at K264 (P = 0.021);.;
MVP
1.0
ClinPred
0.99
D
GERP RS
5.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.88
gMVP
0.94

Splicing

Name
Calibrated prediction
Score
Prediction
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.

Other links and lift over

dbSNP: rs1557194488; hg19: chrX-153649254; API