7-66240627-G-T

Position:

• chr7-66240627-G-T

Variant summary

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

The NM_003596.4(TPST1):​c.202G>T​(p.Asp68Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: TPST1 NM_003596.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.79

Genes affected

TPST1 (HGNC:12020): (tyrosylprotein sulfotransferase 1) Enables protein homodimerization activity and protein-tyrosine sulfotransferase activity. Involved in peptidyl-tyrosine sulfation. Is integral component of Golgi membrane. [provided by Alliance of Genome Resources, Apr 2022]

TPST1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TPST1	NM_003596.4	c.202G>T	p.Asp68Tyr	missense_variant	2/6	ENST00000304842.6	NP_003587.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TPST1	ENST00000304842.6	c.202G>T	p.Asp68Tyr	missense_variant	2/6	1	NM_003596.4	ENSP00000302413.5
TPST1	ENST00000480281.5	n.189+35105G>T		intron_variant		1
TPST1	ENST00000649664.1	c.202G>T	p.Asp68Tyr	missense_variant	3/7			ENSP00000497281.1
TPST1	ENST00000451388.1	c.202G>T	p.Asp68Tyr	missense_variant	2/2	4		ENSP00000391338.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461882 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727244

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 05, 2022

The c.202G>T (p.D68Y) alteration is located in exon 2 (coding exon 1) of the TPST1 gene. This alteration results from a G to T substitution at nucleotide position 202, causing the aspartic acid (D) at amino acid position 68 to be replaced by a tyrosine (Y). 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	Benign	0.17
BayesDel_addAF	Uncertain	0.088	D
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Uncertain	0.52	D;D;.
Eigen	Benign	-0.0066
Eigen_PC	Benign	0.20
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	.;D;D
M_CAP	Benign	0.013	T
MetaRNN	Uncertain	0.47	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L;L;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.5	D;.;D
REVEL	Uncertain	0.29
Sift	Benign	0.15	T;.;T
Sift4G	Benign	0.075	T;.;T
Polyphen		0.0050	B;B;.
Vest4		0.83
MutPred		0.36		Loss of solvent accessibility (P = 0.0509);Loss of solvent accessibility (P = 0.0509);Loss of solvent accessibility (P = 0.0509);
MVP		0.45
MPC		0.35
ClinPred		0.97	D
GERP RS		5.0
Varity_R		0.72
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs752674832; hg19: chr7-65705614; COSMIC: COSV100506911; COSMIC: COSV100506911;