X-154411912-C-T

Variant names:

• chrX-154411912-C-T
• rs782123597
• NM_000116.5:c.69C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 2P and 11B. PM2 BP4_Moderate BP6_Very_Strong BP7

The NM_001440856.1(TAFAZZIN):​c.69C>T​(p.Val23Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000183 in 1,094,255 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. V23V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000018 (0 hom. 0 hem.)
• Consequence: TAFAZZIN NM_001440856.1 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.36
• 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]

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

Our verdict: Benign. The variant received -9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant X-154411912-C-T is Benign according to our data. Variant chrX-154411912-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 462144.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.36 with no splicing effect.

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.69C>T	p.Val23Val	synonymous	Exon 1 of 11	NP_000107.1
	TAFAZZIN	NM_001440856.1		c.69C>T	p.Val23Val	synonymous	Exon 1 of 11	NP_001427785.1
	TAFAZZIN	NM_001303465.2		c.69C>T	p.Val23Val	synonymous	Exon 1 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.69C>T	p.Val23Val	synonymous	Exon 1 of 11	ENSP00000469981.1
	TAFAZZIN	ENST00000475699.6	TSL:1	c.69C>T	p.Val23Val	synonymous	Exon 1 of 10	ENSP00000419854.3
	TAFAZZIN	ENST00000369776.8	TSL:1	c.69C>T	p.Val23Val	synonymous	Exon 1 of 7	ENSP00000358791.4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.0000119 AC: 2 AN: 168308 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000747

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000183 AC: 2 AN: 1094255 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 360987

African (AFR) AF: 0.00 AC: 0 AN: 26364

American (AMR) AF: 0.0000571 AC: 2 AN: 35042

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19299

East Asian (EAS) AF: 0.00 AC: 0 AN: 30122

South Asian (SAS) AF: 0.00 AC: 0 AN: 53701

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38803

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4114

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 840893

Other (OTH) AF: 0.00 AC: 0 AN: 45917

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	3-Methylglutaconic aciduria type 2 (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	15
DANN	Benign	0.95
PhyloP100		1.4
PromoterAI		-0.076	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs782123597; hg19: chrX-153640249;