X-154411872-C-G

Variant names:

• chrX-154411872-C-G
• rs781941217
• NM_000116.5:c.29C>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 6P and 4B. PM1 PP3_Strong BS2

The NM_000116.5(TAFAZZIN):​c.29C>G​(p.Pro10Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000275 in 1,089,756 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000028 (0 hom. 2 hem.)
• Consequence: TAFAZZIN NM_000116.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 5.04

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 6 pathogenic changes around while only 0 benign (100%) in NM_000116.5
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.963
• BS2: High Hemizygotes in GnomAdExome4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TAFAZZIN	NM_000116.5	c.29C>G	p.Pro10Arg	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.29C>G	p.Pro10Arg	missense_variant	Exon 1 of 11	1	NM_000116.5	ENSP00000469981.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 0.00000275 AC: 3 AN: 1089756 Hom.: 0 Cov.: 31 AF XY: 0.00000558 AC XY: 2 AN XY: 358446

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: 0.00000238

Gnomad4 OTH exome AF: 0.0000218

GnomAD4 genome Cov.: 24

ExAC AF: 0.00000837 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

3-Methylglutaconic aciduria type 2 Uncertain:3

May 03, 2020

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 04, 2021

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 08, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 691831). This missense change has been observed in individual(s) with cardiomyopathy (PMID: 31568572). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 10 of the TAZ protein (p.Pro10Arg). -

not provided Uncertain:1

May 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TAFAZZIN: PM2 -

Left ventricular noncompaction cardiomyopathy Uncertain:1

Jul 03, 2019

Klaassen Lab, Charite University Medicine Berlin

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Pathogenic	0.65	D
BayesDel_noAF	Pathogenic	0.69
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	.;.;.;.;.;T;.;T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	.;D;D;.;D;D;D;D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Uncertain	2.7	.;M;M;.;M;M;.;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-7.2	.;.;D;.;.;.;D;D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0020	.;.;D;.;.;.;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D
Polyphen		1.0	.;D;D;.;D;D;.;.
Vest4		0.73, 0.66, 0.70, 0.63, 0.49
MutPred		0.76		Gain of MoRF binding (P = 0.0103);Gain of MoRF binding (P = 0.0103);Gain of MoRF binding (P = 0.0103);Gain of MoRF binding (P = 0.0103);Gain of MoRF binding (P = 0.0103);Gain of MoRF binding (P = 0.0103);Gain of MoRF binding (P = 0.0103);Gain of MoRF binding (P = 0.0103);
MVP		0.99
ClinPred		1.0	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.92
gMVP		0.79

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: rs781941217; hg19: chrX-153640209;