chrX-154414113-T-C

Variant names:

• chrX-154414113-T-C
• rs146934311
• NM_000116.5:c.383T>C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_001440856.1(TAFAZZIN):​c.437T>C​(p.Phe146Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00304 in 1,204,023 control chromosomes in the GnomAD database, including 64 homozygotes. There are 925 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 0.016 (28 hom., 414 hem., cov: 23)
  • Exomes 𝑓: 0.0017 (36 hom. 511 hem.)
• Consequence: TAFAZZIN NM_001440856.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: 0.303
• Publications: 7 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 -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 7 uncertain in NM_001440856.1
• BP4: Computational evidence support a benign effect (MetaRNN=0.0038991868).
• BP6: Variant X-154414113-T-C is Benign according to our data. Variant chrX-154414113-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 42259.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0538 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001440856.1. 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.383T>C	p.Phe128Ser	missense	Exon 5 of 11	NP_000107.1
	TAFAZZIN	NM_001440856.1		c.437T>C	p.Phe146Ser	missense	Exon 5 of 11	NP_001427785.1
	TAFAZZIN	NM_001303465.2		c.437T>C	p.Phe146Ser	missense	Exon 5 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.383T>C	p.Phe128Ser	missense	Exon 5 of 11	ENSP00000469981.1
	TAFAZZIN	ENST00000475699.6	TSL:1	c.424+546T>C		intron	N/A	ENSP00000419854.3
	TAFAZZIN	ENST00000369776.8	TSL:1	c.295+546T>C		intron	N/A	ENSP00000358791.4

Frequencies

GnomAD3 genomes AF: 0.0162 AC: 1786 AN: 110076 Hom.: 28 Cov.: 23

Gnomad AFR AF: 0.0563

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00554

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000152

Gnomad OTH AF: 0.0177

GnomAD2 exomes AF: 0.00457 AC: 831 AN: 182022 AF XY: 0.00275

Gnomad AFR exome AF: 0.0568

Gnomad AMR exome AF: 0.00245

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000160

Gnomad OTH exome AF: 0.00245

GnomAD4 exome AF: 0.00172 AC: 1881 AN: 1093889 Hom.: 36 Cov.: 29 AF XY: 0.00142 AC XY: 511 AN XY: 359485

African (AFR) AF: 0.0592 AC: 1559 AN: 26317

American (AMR) AF: 0.00284 AC: 100 AN: 35177

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19346

East Asian (EAS) AF: 0.00 AC: 0 AN: 30175

South Asian (SAS) AF: 0.0000556 AC: 3 AN: 53923

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40486

Middle Eastern (MID) AF: 0.00222 AC: 9 AN: 4049

European-Non Finnish (NFE) AF: 0.0000549 AC: 46 AN: 838477

Other (OTH) AF: 0.00357 AC: 164 AN: 45939

GnomAD4 genome AF: 0.0162 AC: 1783 AN: 110134 Hom.: 28 Cov.: 23 AF XY: 0.0128 AC XY: 414 AN XY: 32400

African (AFR) AF: 0.0561 AC: 1692 AN: 30181

American (AMR) AF: 0.00553 AC: 57 AN: 10309

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2625

East Asian (EAS) AF: 0.00 AC: 0 AN: 3491

South Asian (SAS) AF: 0.00 AC: 0 AN: 2548

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5878

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.000152 AC: 8 AN: 52724

Other (OTH) AF: 0.0175 AC: 26 AN: 1487

Alfa AF: 0.00344 Hom.: 38

Bravo AF: 0.0191

ESP6500AA AF: 0.0524 AC: 201

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.00535 AC: 650

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	5	not specified (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
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.13
CADD	Benign	6.1
DANN	Benign	0.88
DEOGEN2	Benign	0.31	T
FATHMM_MKL	Benign	0.027	N
LIST_S2	Benign	0.35	T
MetaRNN	Benign	0.0039	T
MetaSVM	Uncertain	0.27	D
MutationAssessor	Benign	1.6	L
PhyloP100		0.30
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.34
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.045	D
Polyphen		0.0	B
Vest4		0.29
MVP		0.68
ClinPred		0.0088	T
GERP RS		-0.54
Varity_R		0.13
gMVP		0.95
Mutation Taster		=98/2	polymorphism (auto)

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: rs146934311; hg19: chrX-153642450;