NM_000116.5:c.352T>C

Variant names:

• chrX-154413549-T-C
• rs104894937
• NM_000116.5:c.352T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_000116.5(TAFAZZIN):​c.352T>C​(p.Cys118Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: TAFAZZIN NM_000116.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 7.19
• Publications: 10 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]

TAFAZZIN Gene-Disease associations (from GenCC):

• Barth syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 3 uncertain in NM_000116.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000116.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TAFAZZIN	NM_000116.5	MANE Select	c.352T>C	p.Cys118Arg	missense	Exon 4 of 11	NP_000107.1
	TAFAZZIN	NM_001440856.1		c.406T>C	p.Cys136Arg	missense	Exon 4 of 11	NP_001427785.1
	TAFAZZIN	NM_001303465.2		c.406T>C	p.Cys136Arg	missense	Exon 4 of 10	NP_001290394.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TAFAZZIN	ENST00000601016.6	TSL:1 MANE Select	c.352T>C	p.Cys118Arg	missense	Exon 4 of 11	ENSP00000469981.1
	TAFAZZIN	ENST00000475699.6	TSL:1	c.406T>C	p.Cys136Arg	missense	Exon 4 of 10	ENSP00000419854.3
	TAFAZZIN	ENST00000369776.8	TSL:1	c.277T>C	p.Cys93Arg	missense	Exon 3 of 7	ENSP00000358791.4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

Alfa AF: 0.000269 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

3-Methylglutaconic aciduria type 2 Pathogenic:1 Uncertain:1

Aug 17, 2020

Molecular Diagnostics Lab, Nemours Children's Health, Delaware

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 06, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.70	D
BayesDel_noAF	Pathogenic	0.77
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		7.2
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-9.9	D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.93
MutPred		0.91		Gain of solvent accessibility (P = 0.0171)
MVP		1.0
ClinPred		1.0	D
GERP RS		5.8
PromoterAI		-0.017	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		1.0
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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

Other links and lift over

dbSNP: rs104894937; hg19: chrX-153641886;