X-154419617-C-G

Position:

chrX-154419617-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 6P and 4B. PM1PP3_StrongBS2

The NM_000116.5(TAFAZZIN):c.535C>G(p.Pro179Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000033 in 1,210,693 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 1 hem., cov: 24)

Exomes 𝑓: 0.0000027 ( 0 hom. 2 hem. )

Consequence

TAFAZZIN
NM_000116.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 7.25

Variant links:

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 links:

TAFAZZIN (HGNC:):

TAFAZZIN links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1

In a region_of_interest Mitochondrial targeting sequence (size 35) in uniprot entity TAZ_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000116.5

PP3

MetaRNN computational evidence supports a deleterious effect, 0.988

BS2

High Hemizygotes in GnomAdExome4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TAFAZZIN	NM_000116.5 linkuse as main transcript	c.535C>G	p.Pro179Ala	missense_variant	6/11	ENST00000601016.6	NP_000107.1	Q16635-1A0A0S2Z4K0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TAFAZZIN	ENST00000601016.6 linkuse as main transcript	c.535C>G	p.Pro179Ala	missense_variant	6/11	1	NM_000116.5	ENSP00000469981.1		Q16635-1

Frequencies

GnomAD3 genomes

AF:

0.00000889

AC:

AN:

112533

Hom.:

Cov.:

AF XY:

0.0000288

AC XY:

AN XY:

34719

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000545

AC:

AN:

183483

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

67911

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000122

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000273

AC:

AN:

1098160

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

363518

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000356

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000889

AC:

AN:

112533

Hom.:

Cov.:

AF XY:

0.0000288

AC XY:

AN XY:

34719

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000188

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

3-Methylglutaconic aciduria type 2

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 12, 2023	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 42261). This missense change has been observed in individual(s) with sudden infant death syndrome (PMID: 26350513). This variant is present in population databases (rs397515744, gnomAD 0.001%). This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 179 of the TAZ protein (p.Pro179Ala). -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 10, 2023

The p.Pro179Ala variant in TAZ has been reported in 1 individual with hypertrophic cardiomyopathy (HCM; LMM data) and 1 individual with sudden unexplained death in infancy (SUDI; Hertz 2016 PMID: 26350513). In the former, the variant did not segregate with HCM in 1 affected family member (LMM data). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 42261) and has been identified in 0.002% (1/53114) of European chromosomes by gnomAD (https://gnomad.broadinstitute.org, v.3.1.2). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while the clinical significance of this variant is uncertain, these data suggest that it is more likely to be benign ACMG/AMP Criteria applied: PM2_Supporting, PP3. -

Left ventricular noncompaction cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Primary dilated cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Endocardial fibroelastosis

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.70

BayesDel_noAF

Pathogenic

0.76

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.92

.;.;.;.;D;.;D

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.88

D;D;.;D;D;D;D

M_CAP

Pathogenic

0.94

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.5

.;M;.;.;M;.;.

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-7.2

.;.;.;.;.;D;D

REVEL

Pathogenic

0.97

Sift

Uncertain

0.0040

.;.;.;.;.;D;D

Sift4G

Uncertain

0.018

D;D;D;D;D;D;D

Polyphen

0.84

P;D;.;P;D;.;.

Vest4

0.75

MutPred

0.87

.;Loss of methylation at K182 (P = 0.0618);.;.;Loss of methylation at K182 (P = 0.0618);.;.;

MVP

1.0

ClinPred

0.98

GERP RS

5.5

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.6

Varity_R

0.73

gMVP

1.0

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over