X-154411861-G-C

Variant names:

• chrX-154411861-G-C
• NM_000116.5:c.18G>C

Variant summary

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

The NM_000116.5(TAFAZZIN):​c.18G>C​(p.Lys6Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000092 in 1,086,653 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 9.2e-7 (0 hom. 0 hem.)
• Consequence: TAFAZZIN NM_000116.5 missense
• Clinical Significance: Not reported in ClinVar
• 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 4 ACMG points.

• PM1: In a chain Tafazzin (size 261) in uniprot entity TAZ_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_000116.5
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TAFAZZIN	NM_000116.5	c.18G>C	p.Lys6Asn	missense_variant	Exon 1 of 11	ENST00000601016.6	NP_000107.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TAFAZZIN	ENST00000601016.6	c.18G>C	p.Lys6Asn	missense_variant	Exon 1 of 11	1	NM_000116.5	ENSP00000469981.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 9.20e-7 AC: 1 AN: 1086653 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 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: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 24

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Uncertain	0.012	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	17
DANN	Benign	0.96
DEOGEN2	Benign	0.17	.;.;.;.;.;T;.;T
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.90	.;D;D;.;D;D;D;D
M_CAP	Pathogenic	0.77	D
MetaRNN	Uncertain	0.48	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.71	D
MutationAssessor	Benign	1.5	.;L;L;.;L;L;.;.
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		0.18	T
GERP RS		-2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.10
gMVP		0.81

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-153640198;