rs121913038

Positions:

chr22-50528571-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_001953.5(TYMP):c.457G>A(p.Gly153Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,613,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

TYMP
NM_001953.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 3.25

Variant links:

Genes affected

TYMP (HGNC:3148): (thymidine phosphorylase) This gene encodes an angiogenic factor which promotes angiogenesis in vivo and stimulates the in vitro growth of a variety of endothelial cells. It has a highly restricted target cell specificity acting only on endothelial cells. Mutations in this gene have been associated with mitochondrial neurogastrointestinal encephalomyopathy. Multiple alternatively spliced transcript variants have been identified. [provided by RefSeq, Apr 2012]

TYMP links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.992

PP5

Variant 22-50528571-C-T is Pathogenic according to our data. Variant chr22-50528571-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 16660.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-50528571-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TYMP	NM_001953.5 linkuse as main transcript	c.457G>A	p.Gly153Ser	missense_variant	4/10	ENST00000252029.8	NP_001944.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TYMP	ENST00000252029.8 linkuse as main transcript	c.457G>A	p.Gly153Ser	missense_variant	4/10	1	NM_001953.5	ENSP00000252029	P2	P19971-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251142

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135826

show subpopulations

Gnomad AFR exome

AF:

0.0000617

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1461644

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727126

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000144

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Mitochondrial DNA depletion syndrome 1

Pathogenic:4

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 29, 1999	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 07, 2024	- -
Pathogenic, no assertion criteria provided	literature only	GeneReviews	Jan 14, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 09, 2021	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 12, 2023	PP3, PP4, PM2, PM3_strong, PS4_moderate -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 153 of the TYMP protein (p.Gly153Ser). This variant is present in population databases (rs121913038, gnomAD 0.007%). This missense change has been observed in individual(s) with mitochondrial neurogastrointestinal encephalomyopathy (PMID: 9924029, 16178026). ClinVar contains an entry for this variant (Variation ID: 16660). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TYMP protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

Mitochondrial neurogastrointestinal encephalomyopathy

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Jan 23, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.64

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.52

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.98

D;.;D;D

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Benign

0.64

LIST_S2

Uncertain

0.96

.;D;.;D

M_CAP

Pathogenic

0.48

MetaRNN

Pathogenic

0.99

D;D;D;D

MetaSVM

Pathogenic

0.93

MutationAssessor

Pathogenic

3.4

M;M;M;M

MutationTaster

Benign

1.0

A;A;A;A

PrimateAI

Benign

0.34

PROVEAN

Pathogenic

-5.9

D;D;D;D

REVEL

Pathogenic

0.92

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

D;.;D;D

Vest4

0.87

MutPred

0.99

Gain of glycosylation at G153 (P = 0.0894);Gain of glycosylation at G153 (P = 0.0894);Gain of glycosylation at G153 (P = 0.0894);Gain of glycosylation at G153 (P = 0.0894);

MVP

0.98

MPC

1.3

ClinPred

1.0

GERP RS

3.6

Varity_R

0.94

gMVP

0.92

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over