rs121913039

chr22-50527612-C-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2 PM5 PP3 PP5_Very_Strong

The NM_001953.5(TYMP):c.622G>A(p.Val208Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000441 in 1,613,832 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V208G) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00046 (0 hom.)
• Consequence: TYMP NM_001953.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 2.33

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]

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr22-50527611-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1999762.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.839
• PP5: Variant 22-50527612-C-T is Pathogenic according to our data. Variant chr22-50527612-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 16663.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TYMP	NM_001953.5	c.622G>A	p.Val208Met	missense_variant	5/10	ENST00000252029.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TYMP	ENST00000252029.8	c.622G>A	p.Val208Met	missense_variant	5/10	1	NM_001953.5	P2

Frequencies

GnomAD3 genomes AF: 0.000243 AC: 37 AN: 152174 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000217

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: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000326 AC: 82 AN: 251306 Hom.: 0 AF XY: 0.000339 AC XY: 46 AN XY: 135874

Gnomad AFR exome AF: 0.000370

Gnomad AMR exome AF: 0.000173

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: 0.000581

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000462 AC: 675 AN: 1461658 Hom.: 0 Cov.: 35 AF XY: 0.000457 AC XY: 332 AN XY: 727130

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000564

Gnomad4 NFE exome AF: 0.000589

Gnomad4 OTH exome AF: 0.000132

GnomAD4 genome AF: 0.000243 AC: 37 AN: 152174 Hom.: 0 Cov.: 33 AF XY: 0.000215 AC XY: 16 AN XY: 74332

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000397

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000435 Hom.: 0

Bravo AF: 0.000196

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000346 AC: 42

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000296

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mitochondrial DNA depletion syndrome 1 Pathogenic:8

Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2005	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 19, 2024	Variant summary: TYMP c.622G>A (p.Val208Met) results in a conservative amino acid change located in the Glycosyl transferase, family 3 domain (IPR000312) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00033 in 251306 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in TYMP causing Mitochondrial DNA Depletion Syndrome 1 (MNGIE type) (0.00033 vs 0.0011), allowing no conclusion about variant significance. c.622G>A has been reported in the literature in individuals affected with Mitochondrial DNA Depletion Syndrome 1 (MNGIE type; Marti_2005, Ronchi_2020, Levy_2021). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 16178026, 32849836, 33300680). ClinVar contains an entry for this variant (Variation ID: 16663). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Pathophysiology and Transplantation, University of Milan	Jul 04, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 25, 2023	- -
Pathogenic, no assertion criteria provided	literature only	GeneReviews	Jan 14, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 03, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 16, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 11, 2022	- -

not provided Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 15, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 30, 2022	Reported with another pathogenic variant in a patient with adult-onset ptosis and ophthalmoparesis and decreased thymidine phosphorylase activity, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (Ronchi et al., 2020); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 16178026, 19853446, 19748572, 21412940, 30487145, 32849836, 32384880, 34426522, 33300680) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 208 of the TYMP protein (p.Val208Met). This variant is present in population databases (rs121913039, gnomAD 0.06%). This missense change has been observed in individual(s) with mitochondrial disease and/or mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) (PMID: 16178026, 32849836, 33300680). ClinVar contains an entry for this variant (Variation ID: 16663). 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. Studies have shown that this missense change alters TYMP gene expression (PMID: 32849836). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.50
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D;.;D;D;D
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.92	D
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.84	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.6	H;H;H;H;.
MutationTaster	Benign	0.98	A;A;A;A
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-2.9	D;D;D;D;D
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	D;.;D;D;.
Vest4		0.75
MVP		0.92
MPC		1.3
ClinPred		0.78	D
GERP RS		3.0
Varity_R		0.93
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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

Other links and lift over

dbSNP: rs121913039; hg19: chr22-50966041;