rs1057515818

Variant names:

• chrX-154419586-G-A
• rs1057515818
• NM_000116.5:c.504G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_000116.5(TAFAZZIN):​c.504G>A​(p.Lys168Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000546 in 1,098,233 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000055 (0 hom. 4 hem.)
• Consequence: TAFAZZIN NM_000116.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:2
• Conservation: PhyloP100: 0.0700
• 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: ClinGen, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant X-154419586-G-A is Benign according to our data. Variant chrX-154419586-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 368087.
• BP7: Synonymous conserved (PhyloP=0.07 with no splicing effect.
• BS2: High Hemizygotes in GnomAdExome4 at 4 XL gene

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.504G>A	p.Lys168Lys	synonymous	Exon 6 of 11	NP_000107.1
	TAFAZZIN	NM_001440856.1		c.558G>A	p.Lys186Lys	synonymous	Exon 6 of 11	NP_001427785.1
	TAFAZZIN	NM_001303465.2		c.558G>A	p.Lys186Lys	synonymous	Exon 6 of 10	NP_001290394.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TAFAZZIN	ENST00000601016.6	TSL:1 MANE Select	c.504G>A	p.Lys168Lys	synonymous	Exon 6 of 11	ENSP00000469981.1
	TAFAZZIN	ENST00000475699.6	TSL:1	c.468G>A	p.Lys156Lys	synonymous	Exon 5 of 10	ENSP00000419854.3
	TAFAZZIN	ENST00000369776.8	TSL:1	c.339G>A	p.Lys113Lys	synonymous	Exon 4 of 7	ENSP00000358791.4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000546 AC: 6 AN: 1098233 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 4 AN XY: 363591

African (AFR) AF: 0.00 AC: 0 AN: 26403

American (AMR) AF: 0.00 AC: 0 AN: 35202

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19386

East Asian (EAS) AF: 0.00 AC: 0 AN: 30206

South Asian (SAS) AF: 0.00 AC: 0 AN: 54148

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40534

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4128

European-Non Finnish (NFE) AF: 0.00000712 AC: 6 AN: 842132

Other (OTH) AF: 0.00 AC: 0 AN: 46094

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	3-Methylglutaconic aciduria type 2 (2)
-	1	-	Endocardial fibroelastosis (1)
-	1	-	Left ventricular noncompaction cardiomyopathy (1)
-	-	1	not provided (1)
-	1	-	Primary dilated cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	7.3
DANN	Benign	0.60
PhyloP100		0.070
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Other links and lift over

dbSNP: rs1057515818; hg19: chrX-153647925;