rs397515743

Variant names:

• chrX-154411891-C-G
• rs397515743
• ENST00000309585.9:c.-173G>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 2P and 12B. PP3_Moderate BP6_Very_Strong BS2

The ENST00000309585.9(DNASE1L1):​c.-173G>C variant causes a splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000415 in 1,205,714 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., 2 hem., cov: 23)
  • Exomes 𝑓: 0.0000018 (0 hom. 0 hem.)
• Consequence: DNASE1L1 ENST00000309585.9 splice_region
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.652
• Publications: 1 publications found

Genes affected

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]

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 -10 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant X-154411891-C-G is Benign according to our data. Variant chrX-154411891-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 42260.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAd4 at 2 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000309585.9. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TAFAZZIN	NM_000116.5	MANE Select	c.48C>G	p.Thr16Thr	synonymous	Exon 1 of 11	NP_000107.1
	DNASE1L1	NM_001009932.3		c.-431G>C		splice_region	Exon 1 of 10	NP_001009932.1
	DNASE1L1	NM_001009933.3		c.-173G>C		splice_region	Exon 1 of 9	NP_001009933.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNASE1L1	ENST00000309585.9	TSL:1	c.-173G>C		splice_region	Exon 1 of 9	ENSP00000309168.5
	TAFAZZIN	ENST00000601016.6	TSL:1 MANE Select	c.48C>G	p.Thr16Thr	synonymous	Exon 1 of 11	ENSP00000469981.1
	TAFAZZIN	ENST00000475699.6	TSL:1	c.48C>G	p.Thr16Thr	synonymous	Exon 1 of 10	ENSP00000419854.3

Frequencies

GnomAD3 genomes AF: 0.0000267 AC: 3 AN: 112350 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000967

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000605 AC: 1 AN: 165304 AF XY: 0.00

Gnomad AFR exome AF: 0.0000857

Gnomad AMR exome AF: 0.00

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: 1093364 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 360532

African (AFR) AF: 0.0000759 AC: 2 AN: 26359

American (AMR) AF: 0.00 AC: 0 AN: 35028

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19291

East Asian (EAS) AF: 0.00 AC: 0 AN: 30109

South Asian (SAS) AF: 0.00 AC: 0 AN: 53671

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38105

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4090

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 840820

Other (OTH) AF: 0.00 AC: 0 AN: 45891

GnomAD4 genome AF: 0.0000267 AC: 3 AN: 112350 Hom.: 0 Cov.: 23 AF XY: 0.0000579 AC XY: 2 AN XY: 34516

African (AFR) AF: 0.0000967 AC: 3 AN: 31008

American (AMR) AF: 0.00 AC: 0 AN: 10794

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2653

East Asian (EAS) AF: 0.00 AC: 0 AN: 3541

South Asian (SAS) AF: 0.00 AC: 0 AN: 2744

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6209

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 237

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 52968

Other (OTH) AF: 0.00 AC: 0 AN: 1516

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000378

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 specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	14
DANN	Benign	0.88
PhyloP100		0.65
PromoterAI		-0.075	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=265/35	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.85		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.85		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs397515743; hg19: chrX-153640228;