X-154411861-G-T

Position:

• chrX-154411861-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM1

The NM_000116.5(TAFAZZIN):​c.18G>T​(p.Lys6Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000644 in 1,086,653 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000064 (0 hom. 1 hem.)
• Consequence: TAFAZZIN NM_000116.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.263

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]

DNASE1L1 (HGNC:2957): (deoxyribonuclease 1 like 1) This gene encodes a deoxyribonuclease protein that shows high sequence similarity to DNase I. The encoded protein is localized to the endoplasmic reticulum and modified by N-linked glycosylation. Alternate transcriptional splice variants encoding the same protein have been observed. [provided by RefSeq, Jan 2015]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a chain Tafazzin (size 261) in uniprot entity TAZ_HUMAN there are 37 pathogenic changes around while only 4 benign (90%) in NM_000116.5

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TAFAZZIN	NM_000116.5	c.18G>T	p.Lys6Asn	missense_variant	1/11	ENST00000601016.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TAFAZZIN	ENST00000601016.6	c.18G>T	p.Lys6Asn	missense_variant	1/11	1	NM_000116.5

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD3 exomes AF: 0.0000133 AC: 2 AN: 150668 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 49452

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000313

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000644 AC: 7 AN: 1086653 Hom.: 0 Cov.: 31 AF XY: 0.00000280 AC XY: 1 AN XY: 356981

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000834

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 24

ExAC AF: 0.0000168 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

3-Methylglutaconic aciduria type 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 09, 2021

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. 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: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available"). This variant has not been reported in the literature in individuals affected with TAZ-related conditions. This variant is present in population databases (rs782245384, ExAC 0.01%). This sequence change replaces lysine with asparagine at codon 6 of the TAZ protein (p.Lys6Asn). The lysine residue is weakly conserved and there is a moderate physicochemical difference between lysine and asparagine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.055	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Benign	0.17	.;.;.;.;.;T;.;T
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.90	.;D;D;.;D;D;D;D
M_CAP	Pathogenic	0.75	D
MetaRNN	Uncertain	0.45	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.71	D
MutationAssessor	Benign	1.5	.;L;L;.;L;L;.;.
MutationTaster	Benign	0.66	N;N;N;N;N;N;D;D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.2	.;.;N;.;.;.;N;N
REVEL	Uncertain	0.30
Sift	Benign	0.12	.;.;T;.;.;.;T;T
Sift4G	Benign	0.078	T;T;T;T;T;T;T;T
Polyphen		0.0010, 0.029, 0.24, 1.0	.;B;B;.;B;D;.;.
Vest4		0.15, 0.13, 0.17, 0.13, 0.27
MutPred		0.42		Loss of methylation at K6 (P = 3e-04);Loss of methylation at K6 (P = 3e-04);Loss of methylation at K6 (P = 3e-04);Loss of methylation at K6 (P = 3e-04);Loss of methylation at K6 (P = 3e-04);Loss of methylation at K6 (P = 3e-04);Loss of methylation at K6 (P = 3e-04);Loss of methylation at K6 (P = 3e-04);
MVP		0.94
ClinPred		0.078	T
GERP RS		-2.0
Varity_R		0.10
gMVP		0.81

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

Other links and lift over

dbSNP: rs782245384; hg19: chrX-153640198;