X-154411884-C-A

Position:

• chrX-154411884-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_000116.5(TAFAZZIN):​c.41C>A​(p.Pro14Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P14P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: TAFAZZIN NM_000116.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.422

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
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20670581).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TAFAZZIN	NM_000116.5	c.41C>A	p.Pro14Gln	missense_variant	1/11	ENST00000601016.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TAFAZZIN	ENST00000601016.6	c.41C>A	p.Pro14Gln	missense_variant	1/11	1	NM_000116.5

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1092353 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 360013

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 27, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Benign	0.17	.;.;.;.;.;T;.;T
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.82	.;T;T;.;T;T;T;T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.21	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.46	D
MutationAssessor	Benign	1.2	.;L;L;.;L;L;.;.
MutationTaster	Benign	0.99	N;N;N;N;N;N;D;D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.23	.;.;N;.;.;.;N;N
REVEL	Uncertain	0.45
Sift	Benign	0.54	.;.;T;.;.;.;T;T
Sift4G	Benign	0.29	T;T;T;T;T;T;T;T
Polyphen		0.0050, 0.026, 0.036, 0.88	.;B;B;.;B;P;.;.
Vest4		0.27, 0.25, 0.29, 0.23, 0.22
MutPred		0.41		Loss of catalytic residue at P13 (P = 0.0116);Loss of catalytic residue at P13 (P = 0.0116);Loss of catalytic residue at P13 (P = 0.0116);Loss of catalytic residue at P13 (P = 0.0116);Loss of catalytic residue at P13 (P = 0.0116);Loss of catalytic residue at P13 (P = 0.0116);Loss of catalytic residue at P13 (P = 0.0116);Loss of catalytic residue at P13 (P = 0.0116);
MVP		0.91
ClinPred		0.22	T
GERP RS		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.056
gMVP		0.42

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-153640221;