20-13390451-G-C

Variant names:

• chr20-13390451-G-C
• rs2041230291
• NM_017714.3:c.1172C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_017714.3(TASP1):​c.1172C>G​(p.Thr391Ser) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000479 in 1,461,200 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: TASP1 NM_017714.3 missense, splice_region
• Scores: Splicing: ADA: 0.0006708
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.73

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17222327).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TASP1	NM_017714.3	c.1172C>G	p.Thr391Ser	missense_variant, splice_region_variant	Exon 14 of 14	ENST00000337743.9	NP_060184.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TASP1	ENST00000337743.9	c.1172C>G	p.Thr391Ser	missense_variant, splice_region_variant	Exon 14 of 14	1	NM_017714.3	ENSP00000338624.4
TASP1	ENST00000480436.5	n.1243C>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 14 of 14	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461200 Hom.: 0 Cov.: 30 AF XY: 0.00000550 AC XY: 4 AN XY: 726896

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: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Feb 15, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1172C>G (p.T391S) alteration is located in exon 14 (coding exon 13) of the TASP1 gene. This alteration results from a C to G substitution at nucleotide position 1172, causing the threonine (T) at amino acid position 391 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Uncertain	0.096	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	21
DANN	Benign	0.86
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.14
Eigen_PC	Benign	0.086
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.084	D
MetaRNN	Benign	0.17	T
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Benign	0.98	L
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.32	N
REVEL	Benign	0.23
Sift	Benign	0.66	T
Sift4G	Benign	0.62	T
Polyphen		0.039	B
Vest4		0.34
MutPred		0.45		Loss of sheet (P = 0.0315);
MVP		0.16
MPC		0.48
ClinPred		0.49	T
GERP RS		5.0
Varity_R		0.31
gMVP		0.59

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00067
dbscSNV1_RF	Benign	0.030
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

Other links and lift over

dbSNP: rs2041230291; hg19: chr20-13371098;