chr7-66286519-G-T

Variant names:

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

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>T​(p.Arg285Ile) 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)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• 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, 0.754

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPST1	NM_003596.4	c.854G>T	p.Arg285Ile	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>T	p.Arg285Ile	missense_variant	Exon 3 of 6	1	NM_003596.4	ENSP00000302413.5
TPST1	ENST00000480281.5	n.198G>T		non_coding_transcript_exon_variant	Exon 2 of 5	1
TPST1	ENST00000649664.1	c.854G>T	p.Arg285Ile	missense_variant	Exon 4 of 7			ENSP00000497281.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1438664 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 715698

African (AFR) AF: 0.00 AC: 0 AN: 32566

American (AMR) AF: 0.00 AC: 0 AN: 42886

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25554

East Asian (EAS) AF: 0.00 AC: 0 AN: 38208

South Asian (SAS) AF: 0.00 AC: 0 AN: 82850

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52512

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5666

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1099258

Other (OTH) AF: 0.00 AC: 0 AN: 59164

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	29
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.64	D;D
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.99	.;D
M_CAP	Benign	0.047	D
MetaRNN	Pathogenic	0.75	D;D
MetaSVM	Benign	-0.49	T
MutationAssessor	Pathogenic	2.9	M;M
PhyloP100		6.8
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-6.8	D;.
REVEL	Uncertain	0.55
Sift	Uncertain	0.0090	D;.
Sift4G	Benign	0.084	T;.
Polyphen		0.66	P;P
Vest4		0.64
MutPred		0.51		Loss of disorder (P = 0.0257);Loss of disorder (P = 0.0257);
MVP		0.37
MPC		0.99
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.72
gMVP		0.75
Mutation Taster		=47/53	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;