X-154411756-G-C

Variant names:

• chrX-154411756-G-C
• rs113130344
• NM_000116.5:c.-88G>C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000116.5(TAFAZZIN):​c.-88G>C variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0121 in 893,447 control chromosomes in the GnomAD database, including 80 homozygotes. There are 3,182 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 0.010 (6 hom., 341 hem., cov: 24)
  • Exomes 𝑓: 0.012 (74 hom. 2841 hem.)
• Consequence: TAFAZZIN NM_000116.5 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.136

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]

DNASE1L1 (HGNC:2957): (deoxyribonuclease 1 like 1) This gene encodes a deoxyribonuclease protein that shows high sequence similarity to DNase I. The encoded protein is localized to the endoplasmic reticulum and modified by N-linked glycosylation. Alternate transcriptional splice variants encoding the same protein have been observed. [provided by RefSeq, Jan 2015]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant X-154411756-G-C is Benign according to our data. Variant chrX-154411756-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 368086.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154411756-G-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0101 (1131/112499) while in subpopulation NFE AF= 0.0159 (839/52913). AF 95% confidence interval is 0.015. There are 6 homozygotes in gnomad4. There are 341 alleles in male gnomad4 subpopulation. Median coverage is 24. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 6 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TAFAZZIN	NM_000116.5	c.-88G>C		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 11	ENST00000601016.6	NP_000107.1
TAFAZZIN	NM_000116.5	c.-88G>C		5_prime_UTR_variant	Exon 1 of 11	ENST00000601016.6	NP_000107.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TAFAZZIN	ENST00000601016	c.-88G>C		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 11	1	NM_000116.5	ENSP00000469981.1
TAFAZZIN	ENST00000601016	c.-88G>C		5_prime_UTR_variant	Exon 1 of 11	1	NM_000116.5	ENSP00000469981.1

Frequencies

GnomAD3 genomes AF: 0.0101 AC: 1133 AN: 112454 Hom.: 6 Cov.: 24 AF XY: 0.00983 AC XY: 341 AN XY: 34684

Gnomad AFR AF: 0.00209

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00378

Gnomad ASJ AF: 0.00984

Gnomad EAS AF: 0.000284

Gnomad SAS AF: 0.00286

Gnomad FIN AF: 0.0192

Gnomad MID AF: 0.0422

Gnomad NFE AF: 0.0159

Gnomad OTH AF: 0.0151

GnomAD3 exomes AF: 0.00825 AC: 746 AN: 90435 Hom.: 4 AF XY: 0.00831 AC XY: 275 AN XY: 33089

Gnomad AFR exome AF: 0.00187

Gnomad AMR exome AF: 0.00252

Gnomad ASJ exome AF: 0.00925

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00146

Gnomad FIN exome AF: 0.0237

Gnomad NFE exome AF: 0.0149

Gnomad OTH exome AF: 0.00766

GnomAD4 exome AF: 0.0124 AC: 9650 AN: 780948 Hom.: 74 Cov.: 13 AF XY: 0.0131 AC XY: 2841 AN XY: 216558

Gnomad4 AFR exome AF: 0.00176

Gnomad4 AMR exome AF: 0.00319

Gnomad4 ASJ exome AF: 0.00925

Gnomad4 EAS exome AF: 0.0000392

Gnomad4 SAS exome AF: 0.00179

Gnomad4 FIN exome AF: 0.0201

Gnomad4 NFE exome AF: 0.0143

Gnomad4 OTH exome AF: 0.0110

GnomAD4 genome AF: 0.0101 AC: 1131 AN: 112499 Hom.: 6 Cov.: 24 AF XY: 0.00982 AC XY: 341 AN XY: 34739

Gnomad4 AFR AF: 0.00209

Gnomad4 AMR AF: 0.00378

Gnomad4 ASJ AF: 0.00984

Gnomad4 EAS AF: 0.000286

Gnomad4 SAS AF: 0.00288

Gnomad4 FIN AF: 0.0192

Gnomad4 NFE AF: 0.0159

Gnomad4 OTH AF: 0.0149

Alfa AF: 0.0168 Hom.: 134

Bravo AF: 0.00839

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

3-Methylglutaconic aciduria type 2 Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Left ventricular noncompaction cardiomyopathy Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Primary dilated cardiomyopathy Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Endocardial fibroelastosis Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	3.2
DANN	Benign	0.39
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs113130344; hg19: chrX-153640093;