rs149977726

Positions:

chr22-50527265-T-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_001953.5(TYMP):c.665A>G(p.Lys222Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,613,446 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 Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

TYMP
NM_001953.5 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 2.55

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 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.882

PP5

Variant 22-50527265-T-C is Pathogenic according to our data. Variant chr22-50527265-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 16656.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TYMP	NM_001953.5 link	c.665A>G	p.Lys222Arg	missense_variant	6/10	ENST00000252029.8	NP_001944.1	P19971-1E5KRG5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TYMP	ENST00000252029.8 link	c.665A>G	p.Lys222Arg	missense_variant	6/10	1	NM_001953.5	ENSP00000252029.3		P19971-1

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

250636

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135826

show subpopulations

Gnomad AFR exome

AF:

0.000186

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461270

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726952

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000920

AC:

AN:

152176

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.000338

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:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000718

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Mitochondrial DNA depletion syndrome 1

Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2000	- -
Pathogenic, no assertion criteria provided	literature only	GeneReviews	Jan 14, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 29, 2024	- -

not provided

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 21, 2023	This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 222 of the TYMP protein (p.Lys222Arg). This variant is present in population databases (rs149977726, gnomAD 0.03%). This missense change has been observed in individual(s) with mitochondrial neurogastrointestinal encephalopathy (PMID: 9924029). This variant is also known as A2744G. ClinVar contains an entry for this variant (Variation ID: 16656). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TYMP protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 09, 2016	The K222R variant in the TYMP gene has previously been reported association with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) syndrome in an individual who was also heterozygous for frameshift variant in TYMP although the phase of these variants was not determined (Giordano et al., 2008). The K222R variant was not observed at any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The K222R variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species and is predicted to be involved in phosphate binding within the activite site of the thymidine phosphorylase enzyme (Nishino et al., 1999; Pugmire et al., 1998). Additionally, in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. -

Mitochondrial neurogastrointestinal encephalomyopathy

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Jun 29, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.72

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Pathogenic

0.33

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.93

D;.;D;D;D

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.93

.;D;.;D;T

M_CAP

Pathogenic

0.77

MetaRNN

Pathogenic

0.88

D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.1

H;H;H;H;.

PrimateAI

Benign

0.43

PROVEAN

Uncertain

-2.8

D;D;D;D;D

REVEL

Pathogenic

0.79

Sift

Pathogenic

0.0

D;D;D;D;D

Sift4G

Uncertain

0.011

D;D;D;D;D

Polyphen

1.0

D;.;D;D;.

Vest4

0.71

MVP

0.95

MPC

1.0

ClinPred

0.99

GERP RS

3.7

Varity_R

0.96

gMVP

0.87

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