X-154412214-G-C

Variant names:

• chrX-154412214-G-C
• rs1557191170
• NM_000116.5:c.238G>C

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000116.5(TAFAZZIN):​c.238G>C​(p.Gly80Arg) variant causes a missense, splice region 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. 16/27 in silico tools predict a damaging outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar.

• Frequency: Genomes: not found (cov: 24)
• Consequence: TAFAZZIN NM_000116.5 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 8.89
• Publications: 0 publications found

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

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_000116.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant X-154412214-G-C is Pathogenic according to our data. Variant chrX-154412214-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 807698.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TAFAZZIN	NM_000116.5	c.238G>C	p.Gly80Arg	missense_variant, splice_region_variant	Exon 2 of 11	ENST00000601016.6	NP_000107.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TAFAZZIN	ENST00000601016.6	c.238G>C	p.Gly80Arg	missense_variant, splice_region_variant	Exon 2 of 11	1	NM_000116.5	ENSP00000469981.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

3-Methylglutaconic aciduria type 2 Pathogenic:2

Oct 29, 2018

Institute of Human Genetics Munich, TUM University Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Kids Neuroscience Centre, Sydney Children's Hospitals Network

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Use of Intron-2 cryptic 5’ splice-site abnormally includes 36 nt of intron-2 into the TAZ pre-mRNA, encoding 12 ectopic amino acids into the tafazzin protein. Exon-2 skipping abnormally removes 129 nucleotides from the TAZ pre-mRNA. This event is in frame, deleting 43 (highly conserved) amino acids from the encoded tafazzin protein. Our RT-PCR results infer splicing outcomes consistent with a damaging effect for the encoded tafazzin protein. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.70	D
BayesDel_noAF	Pathogenic	0.76
CADD	Pathogenic	40
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.83	.;.;.;.;.;D;D
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	.;D;D;.;D;D;D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	.;M;M;.;M;M;.
PhyloP100		8.9
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-6.3	.;.;D;.;.;.;D
REVEL	Pathogenic	0.98
Sift	Uncertain	0.0010	.;.;D;.;.;.;D
Sift4G	Uncertain	0.0040	D;D;D;D;D;D;D
Polyphen		1.0	.;D;D;.;D;D;.
Vest4		0.88, 0.86, 0.85
MutPred		0.81		.;Gain of MoRF binding (P = 0.029);Gain of MoRF binding (P = 0.029);.;Gain of MoRF binding (P = 0.029);Gain of MoRF binding (P = 0.029);Gain of MoRF binding (P = 0.029);
MVP		1.0
ClinPred		1.0	D
GERP RS		4.0
PromoterAI		0.088	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		1.0
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.98
SpliceAI score (max)		0.67		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.32		Position offset: 36
DS_DL_spliceai		0.67		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1557191170; hg19: chrX-153640551;