rs35902788

Variant names:

• chrX-154420998-G-A
• rs35902788
• NM_000116.5:c.873G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000116.5(TAFAZZIN):​c.873G>A​(p.Gly291Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00449 in 1,207,772 control chromosomes in the GnomAD database, including 10 homozygotes. There are 1,697 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0037 (2 hom., 102 hem., cov: 23)
  • Exomes 𝑓: 0.0046 (8 hom. 1595 hem.)
• Consequence: TAFAZZIN NM_000116.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: 0.100
• Publications: 1 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, PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant X-154420998-G-A is Benign according to our data. Variant chrX-154420998-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 42270.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.1 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00366 (411/112301) while in subpopulation NFE AF = 0.00582 (309/53121). AF 95% confidence interval is 0.00528. There are 2 homozygotes in GnomAd4. There are 102 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.873G>A	p.Gly291Gly	synonymous	Exon 11 of 11	NP_000107.1	Q16635-1
	TAFAZZIN	NM_001440856.1		c.927G>A	p.Gly309Gly	synonymous	Exon 11 of 11	NP_001427785.1
	TAFAZZIN	NM_001303465.2		c.885G>A	p.Gly295Gly	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.873G>A	p.Gly291Gly	synonymous	Exon 11 of 11	ENSP00000469981.1	Q16635-1
	TAFAZZIN	ENST00000475699.6	TSL:1	c.837G>A	p.Gly279Gly	synonymous	Exon 10 of 10	ENSP00000419854.3	A0A499FJ53
	TAFAZZIN	ENST00000369776.8	TSL:1	c.783G>A	p.Gly261Gly	synonymous	Exon 7 of 7	ENSP00000358791.4	F6Y2X3

Frequencies

GnomAD3 genomes AF: 0.00366 AC: 411 AN: 112248 Hom.: 2 Cov.: 23

Gnomad AFR AF: 0.000647

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00536

Gnomad ASJ AF: 0.00113

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00211

Gnomad MID AF: 0.00837

Gnomad NFE AF: 0.00582

Gnomad OTH AF: 0.00464

GnomAD2 exomes AF: 0.00359 AC: 653 AN: 181887 AF XY: 0.00347

Gnomad AFR exome AF: 0.000383

Gnomad AMR exome AF: 0.00314

Gnomad ASJ exome AF: 0.000671

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00245

Gnomad NFE exome AF: 0.00618

Gnomad OTH exome AF: 0.00355

GnomAD4 exome AF: 0.00458 AC: 5014 AN: 1095471 Hom.: 8 Cov.: 30 AF XY: 0.00442 AC XY: 1595 AN XY: 360867

African (AFR) AF: 0.000721 AC: 19 AN: 26351

American (AMR) AF: 0.00327 AC: 115 AN: 35191

Ashkenazi Jewish (ASJ) AF: 0.000465 AC: 9 AN: 19368

East Asian (EAS) AF: 0.00 AC: 0 AN: 30179

South Asian (SAS) AF: 0.000130 AC: 7 AN: 54036

European-Finnish (FIN) AF: 0.00240 AC: 97 AN: 40459

Middle Eastern (MID) AF: 0.00436 AC: 18 AN: 4124

European-Non Finnish (NFE) AF: 0.00541 AC: 4542 AN: 839750

Other (OTH) AF: 0.00450 AC: 207 AN: 46013

GnomAD4 genome AF: 0.00366 AC: 411 AN: 112301 Hom.: 2 Cov.: 23 AF XY: 0.00296 AC XY: 102 AN XY: 34467

African (AFR) AF: 0.000645 AC: 20 AN: 30996

American (AMR) AF: 0.00535 AC: 57 AN: 10654

Ashkenazi Jewish (ASJ) AF: 0.00113 AC: 3 AN: 2651

East Asian (EAS) AF: 0.00 AC: 0 AN: 3568

South Asian (SAS) AF: 0.00 AC: 0 AN: 2715

European-Finnish (FIN) AF: 0.00211 AC: 13 AN: 6166

Middle Eastern (MID) AF: 0.00917 AC: 2 AN: 218

European-Non Finnish (NFE) AF: 0.00582 AC: 309 AN: 53121

Other (OTH) AF: 0.00459 AC: 7 AN: 1526

Alfa AF: 0.00486 Hom.: 158

Bravo AF: 0.00366

EpiCase AF: 0.00583

EpiControl AF: 0.00499

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	5	not provided (5)
-	-	3	3-Methylglutaconic aciduria type 2 (3)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Endocardial fibroelastosis (1)
-	-	1	Left ventricular noncompaction cardiomyopathy (1)
-	-	1	Primary dilated cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	4.7
DANN	Benign	0.57
PhyloP100		0.10
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs35902788; hg19: chrX-153649337;