22-50526639-C-T

Position:

• chr22-50526639-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_001953.5(TYMP):​c.865G>A​(p.Glu289Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000282 in 1,417,480 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E289A) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: TYMP NM_001953.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 3.28

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr22-50526638-T-G is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TYMP	NM_001953.5	c.865G>A	p.Glu289Lys	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.865G>A	p.Glu289Lys	missense_variant	7/10	1	NM_001953.5	ENSP00000252029.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000282 AC: 4 AN: 1417480 Hom.: 0 Cov.: 36 AF XY: 0.00000428 AC XY: 3 AN XY: 701564

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: 0.0000123

Gnomad4 FIN exome AF: 0.0000216

Gnomad4 NFE exome AF: 0.00000183

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Mitochondrial DNA depletion syndrome 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

GeneReviews

Jan 14, 2016

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 18, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the p.Glu289 amino acid residue in TYMP. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9924029, 10852545, 15781193, 20151198, 23341816). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 223044). This missense change has been observed in individual(s) with TYMP-related conditions (PMID: 10852545). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 289 of the TYMP protein (p.Glu289Lys). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.91	D;.;D;D;D
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	.;D;.;D;T
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.0	H;H;H;H;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.5	D;D;D;D;D
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0080	D;D;D;D;D
Sift4G	Uncertain	0.012	D;D;D;D;D
Polyphen		1.0	D;.;D;D;.
Vest4		0.74
MutPred		0.95		Gain of ubiquitination at E289 (P = 0.0211);Gain of ubiquitination at E289 (P = 0.0211);Gain of ubiquitination at E289 (P = 0.0211);Gain of ubiquitination at E289 (P = 0.0211);.;
MVP		0.98
MPC		1.4
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.95
gMVP		0.96

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: rs946234163; hg19: chr22-50965068;