NM_017714.3:c.675+1G>T

Variant names:

• chr20-13559007-C-A
• NM_017714.3:c.675+1G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_017714.3(TASP1):​c.675+1G>T variant causes a splice donor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TASP1 NM_017714.3 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.79
• Publications: 0 publications found

Genes affected

TASP1 (HGNC:15859): (taspase 1) This gene encodes an endopeptidase that cleaves specific substrates following aspartate residues. The encoded protein undergoes posttranslational autoproteolytic processing to generate alpha and beta subunits, which reassemble into the active alpha2-beta2 heterotetramer. It is required to cleave MLL, a protein required for the maintenance of HOX gene expression, and TFIIA, a basal transcription factor. Alternatively spliced transcript variants have been described, but their biological validity has not been determined. [provided by RefSeq, Jul 2008]

TASP1 Gene-Disease associations (from GenCC):

• Suleiman-El-Hattab syndrome

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 20-13559007-C-A is Pathogenic according to our data. Variant chr20-13559007-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1878237.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017714.3. 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
	TASP1	NM_017714.3	MANE Select	c.675+1G>T		splice_donor intron	N/A	NP_060184.2	Q9H6P5-1
	TASP1	NM_001323603.2		c.369+1G>T		splice_donor intron	N/A	NP_001310532.1
	TASP1	NM_001323604.2		c.369+1G>T		splice_donor intron	N/A	NP_001310533.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TASP1	ENST00000337743.9	TSL:1 MANE Select	c.675+1G>T		splice_donor intron	N/A	ENSP00000338624.4	Q9H6P5-1
	TASP1	ENST00000961261.1		c.675+1G>T		splice_donor intron	N/A	ENSP00000631320.1
	TASP1	ENST00000861004.1		c.675+1G>T		splice_donor intron	N/A	ENSP00000531063.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1416254 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 704766

African (AFR) AF: 0.00 AC: 0 AN: 31734

American (AMR) AF: 0.00 AC: 0 AN: 40348

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25246

East Asian (EAS) AF: 0.00 AC: 0 AN: 38424

South Asian (SAS) AF: 0.00 AC: 0 AN: 79114

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52354

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5612

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1085000

Other (OTH) AF: 0.00 AC: 0 AN: 58422

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Suleiman-El-Hattab syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		6.8
GERP RS		5.4
Mutation Taster		=0/100	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.92
SpliceAI score (max)		0.93		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.47		Position offset: -4
DS_DL_spliceai		0.93		Position offset: 1

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

Other links and lift over

hg19: chr20-13539654;