rs1064792872

Positions:

• chr22-50526611-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The ENST00000252029.8(TYMP):​c.893G>A​(p.Gly298Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TYMP ENST00000252029.8 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 1.93

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 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.877
• PP5: Variant 22-50526611-C-T is Pathogenic according to our data. Variant chr22-50526611-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 223046.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	c.893G>A	p.Gly298Asp	missense_variant	7/10	ENST00000252029.8	NP_001944.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TYMP	ENST00000252029.8	c.893G>A	p.Gly298Asp	missense_variant	7/10	1	NM_001953.5	ENSP00000252029	P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1426566 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 706896

Gnomad4 AFR exome AF: 0.00

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 Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mitochondrial DNA depletion syndrome 1 Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	GeneReviews	Jan 14, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 24, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with mitochondrial DNA depletion syndrome 1 (MNGIE type) (MIM#603041). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to aspartic acid. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated glycosyl transferase domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals. The variant has been reported as pathogenic, and observed in at least two unrelated homozygous individuals with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) (GeneReviews, PMID: 21933806, PMID: 21820356, PMID: 21794876). (SP) 0906 - Segregation evidence for this variant is inconclusive. This variant has been observed to segregate within two affected homozygous siblings, however this is insufficient meioses to conclude significant segregation. The third affected sibling was not genotyped (PMID: 21794876). (I) 1001 - This variant has strong functional evidence supporting abnormal protein function. Biochemical analysis of patient plasma has demonstrated null or significantly reduced thymidine phosphorylase activity (PMID: 21794876, PMID: 21820356). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 16, 2023

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. 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. ClinVar contains an entry for this variant (Variation ID: 223046). This missense change has been observed in individual(s) with mitochondrial neurogastrointestinal encephalopathy (PMID: 21794876). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 298 of the TYMP protein (p.Gly298Asp). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D;.;D;D;D
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.71	.;T;.;T;T
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.7	M;M;M;M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-6.2	D;D;D;D;D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.010	D;D;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D;D
Polyphen		1.0	D;.;D;D;.
Vest4		0.60
MutPred		0.45		Loss of catalytic residue at G298 (P = 0.0418);Loss of catalytic residue at G298 (P = 0.0418);Loss of catalytic residue at G298 (P = 0.0418);Loss of catalytic residue at G298 (P = 0.0418);.;
MVP		0.97
MPC		1.4
ClinPred		0.97	D
GERP RS		4.7
Varity_R		0.86
gMVP		0.94

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

Other links and lift over

dbSNP: rs1064792872; hg19: chr22-50965040;