NM_003596.4:c.854G>C

Variant names:

• chr7-66286519-G-C
• rs375107999
• NM_003596.4:c.854G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_003596.4(TPST1):​c.854G>C​(p.Arg285Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R285K) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TPST1 NM_003596.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.84
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.825

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPST1	NM_003596.4	c.854G>C	p.Arg285Thr	missense_variant	Exon 3 of 6	ENST00000304842.6	NP_003587.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPST1	ENST00000304842.6	c.854G>C	p.Arg285Thr	missense_variant	Exon 3 of 6	1	NM_003596.4	ENSP00000302413.5
TPST1	ENST00000480281.5	n.198G>C		non_coding_transcript_exon_variant	Exon 2 of 5	1
TPST1	ENST00000649664.1	c.854G>C	p.Arg285Thr	missense_variant	Exon 4 of 7			ENSP00000497281.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.63	D;D
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	.;D
M_CAP	Benign	0.050	D
MetaRNN	Pathogenic	0.82	D;D
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Pathogenic	2.9	M;M
PhyloP100		6.8
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-5.1	D;.
REVEL	Uncertain	0.41
Sift	Uncertain	0.020	D;.
Sift4G	Benign	0.19	T;.
Polyphen		0.99	D;D
Vest4		0.59
MutPred		0.47		Loss of MoRF binding (P = 0.0305);Loss of MoRF binding (P = 0.0305);
MVP		0.40
MPC		1.0
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.74
gMVP		0.80
Mutation Taster		=45/55	disease causing

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

Other links and lift over

dbSNP: rs375107999; hg19: chr7-65751506; COSMIC: COSV59175842;