X-154420926-G-T

Variant names:

• chrX-154420926-G-T
• rs781792950
• NM_000116.5:c.801G>T
• TAFAZZIN p.Thr267Thr

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM2 BP4_Strong BP6_Very_Strong BP7

The NM_000116.5(TAFAZZIN):​c.801G>T​(p.Thr267Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000182 in 1,097,974 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T267T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000018 (0 hom. 1 hem.)
• Consequence: TAFAZZIN NM_000116.5 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -10.6
• 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]

TAFAZZIN Gene-Disease associations (from GenCC):

• Barth syndrome

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

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BP6: Variant X-154420926-G-T is Benign according to our data. Variant chrX-154420926-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1960429.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-10.6 with no splicing effect.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TAFAZZIN	NM_000116.5	MANE Select	c.801G>T	p.Thr267Thr	synonymous	Exon 11 of 11	NP_000107.1	Q16635-1
	TAFAZZIN	NM_001440856.1		c.855G>T	p.Thr285Thr	synonymous	Exon 11 of 11	NP_001427785.1
	TAFAZZIN	NM_001303465.2		c.813G>T	p.Thr271Thr	synonymous	Exon 10 of 10	NP_001290394.1	A6XNE1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TAFAZZIN	ENST00000601016.6	TSL:1 MANE Select	c.801G>T	p.Thr267Thr	synonymous	Exon 11 of 11	ENSP00000469981.1	Q16635-1
	TAFAZZIN	ENST00000475699.6	TSL:1	c.765G>T	p.Thr255Thr	synonymous	Exon 10 of 10	ENSP00000419854.3	A0A499FJ53
	TAFAZZIN	ENST00000369776.8	TSL:1	c.711G>T	p.Thr237Thr	synonymous	Exon 7 of 7	ENSP00000358791.4	F6Y2X3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000182 AC: 2 AN: 1097974 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 1 AN XY: 363330

African (AFR) AF: 0.00 AC: 0 AN: 26394

American (AMR) AF: 0.0000284 AC: 1 AN: 35202

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19382

East Asian (EAS) AF: 0.00 AC: 0 AN: 30200

South Asian (SAS) AF: 0.0000185 AC: 1 AN: 54123

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40531

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4116

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 841943

Other (OTH) AF: 0.00 AC: 0 AN: 46083

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	3-Methylglutaconic aciduria type 2 (1)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.0070
DANN	Benign	0.52
PhyloP100		-11
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs781792950;

hg19: chrX-153649265;