rs121913036

Positions:

chr22-50526638-T-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong

The NM_001953.5(TYMP):c.866A>C(p.Glu289Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000573 in 1,570,278 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E289K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000059 ( 0 hom. )

Consequence

TYMP
NM_001953.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 3.36

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.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_001953.5

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.853

PP5

Variant 22-50526638-T-G is Pathogenic according to our data. Variant chr22-50526638-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 16653.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-50526638-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TYMP	NM_001953.5 linkuse as main transcript	c.866A>C	p.Glu289Ala	missense_variant	7/10	ENST00000252029.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TYMP	ENST00000252029.8 linkuse as main transcript	c.866A>C	p.Glu289Ala	missense_variant	7/10	1	NM_001953.5	P2	P19971-1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000530

AC:

AN:

169894

Hom.:

AF XY:

0.0000431

AC XY:

AN XY:

92736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000718

Gnomad ASJ exome

AF:

0.000587

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000293

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000585

AC:

AN:

1418162

Hom.:

Cov.:

AF XY:

0.0000513

AC XY:

AN XY:

701966

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000508

Gnomad4 ASJ exome

AF:

0.000473

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000123

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000605

Gnomad4 OTH exome

AF:

0.0000340

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152116

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74306

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000868

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.0000257

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Mitochondrial DNA depletion syndrome 1

Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 08, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 29, 1999	- -
Pathogenic, no assertion criteria provided	literature only	GeneReviews	Jan 14, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 22, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Pathophysiology and Transplantation, University of Milan	Jul 04, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Oct 09, 2018	The TYMP c.866A>C (p.Glu289Ala) missense variant has been reported in at least five studies and is found in a total of 12 individuals with mitochondrial neurogastrointestinal encophalopathy disease (MNGIE), including in at least four in a homozygous state and in eight in a compound heterozygous state (Nishino et al. 1999; Amiot et al. 2009; Bakker et al. 2010; Scarpelli et al. 2012; Finkenstedt et al. 2012). As of 2010, fewer than 70 individuals with features consistent with MNGIE had been reported, according to Gene Reviews (Shoffner, 2010). The p.Glu289Ala variant was absent from 63 control subjects and is reported at a frequency of 0.000604 in the Ashkenazi Jewish population of the Genome Aggregation Database. Assays of TYMP activity level in peripheral leukocytes from six affected individuals, including one homozygote and two compound heterozygotes with the p.Glu289Ala variant, and 19 controls revealed that probands had either no detectable TYMP activity or activity that was less than 5% of controls (Nishino et al. 1999). Based on the evidence, the p.Glu289Ala variant is classified as pathogenic for mitochondrial neurogastrointestinal encophalopathy disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 21, 2023	This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 289 of the TYMP protein (p.Glu289Ala). This variant is present in population databases (rs121913036, gnomAD 0.06%). This missense change has been observed in individuals with TYMP-related conditions (PMID: 9924029, 10852545, 15781193, 20151198, 23341816). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 16653). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 29, 2022	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19344718, 20151198, 10852545, 18787099, 21503690, 9924029, 24199812, 23430799, 23341816, 19748572, 19221117, 31267951, 33300680, 32849836) -

Mitochondrial neurogastrointestinal encephalomyopathy

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.84

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.41

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.91

D;.;D;D;D

Eigen

Pathogenic

0.75

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Pathogenic

0.99

M_CAP

Pathogenic

0.91

MetaRNN

Pathogenic

0.85

D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.0

M;M;M;M;.

MutationTaster

Benign

1.0

A;A;A;A

PrimateAI

Pathogenic

0.84

PROVEAN

Pathogenic

-5.4

D;D;D;D;D

REVEL

Pathogenic

0.96

Sift

Uncertain

0.012

D;D;D;D;D

Sift4G

Uncertain

0.0070

D;D;D;D;D

Polyphen

1.0

D;.;D;D;.

Vest4

0.75

MVP

0.98

MPC

1.3

ClinPred

0.90

GERP RS

4.8

Varity_R

0.89

gMVP

0.93

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

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