22-50525802-AG-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_001953.5(TYMP):c.1416del(p.Phe473SerfsTer?) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000197 in 152,218 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P472P) has been classified as Likely benign.

• Frequency: Genomes: 𝑓 0.000020 (0 hom., cov: 35)
• Consequence: TYMP NM_001953.5 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 0.447

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]

SCO2 (HGNC:10604): (synthesis of cytochrome C oxidase 2) Cytochrome c oxidase (COX) catalyzes the transfer of electrons from cytochrome c to molecular oxygen, which helps to maintain the proton gradient across the inner mitochondrial membrane that is necessary for aerobic ATP production. Human COX is a multimeric protein complex that requires several assembly factors; this gene encodes one of the COX assembly factors. The encoded protein is a metallochaperone that is involved in the biogenesis of cytochrome c oxidase subunit II. Mutations in this gene are associated with fatal infantile encephalocardiomyopathy and myopia 6. [provided by RefSeq, Oct 2014]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0228 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 22-50525802-AG-A is Pathogenic according to our data. Variant chr22-50525802-AG-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 817030.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.1416del	p.Phe473SerfsTer?	frameshift_variant	10/10	ENST00000252029.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TYMP	ENST00000252029.8	c.1416del	p.Phe473SerfsTer?	frameshift_variant	10/10	1	NM_001953.5	P2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152218 Hom.: 0 Cov.: 35

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.000478

GnomAD4 exome Cov.: 38

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152218 Hom.: 0 Cov.: 35 AF XY: 0.0000403 AC XY: 3 AN XY: 74368

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

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: 0.000478

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Mar 18, 2023	For these reasons, this variant has been classified as Pathogenic. Studies have shown that this frameshift alters TYMP gene expression (PMID: 21412940). ClinVar contains an entry for this variant (Variation ID: 817030). This variant is also known as p.F473SfsX41. This frameshift has been observed in individual(s) with mitochondrial neurogastrointestinal encephalomyopathy (PMID: 21412940). This variant is not present in population databases (gnomAD no frequency). This sequence change results in a frameshift in the TYMP gene (p.Phe473Serfs*?). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 10 amino acid(s) of the TYMP protein and extend the protein by an uncertain number of additional amino acid residues. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 18, 2018	The c.1414delC variant has been reported previously in an individual with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) who was homozygous for this change (Torres-Torronteras et al., 2011). The c.1414delC variant causes a frameshift starting with codon Phenylalanine 473, changes this amino acid to a Serine residue and is expected to extend the open reading frame to an unknown length, denoted p.Phe473SerfsX?. Other frameshift variants, including one downstream of c.1414delC, have been reported in the Human Gene Mutation Database in individuals with MNGIE (Stenson et al., 2014). Furthermore, the c.1414delC variant is not observed in large population cohorts (Lek et al., 2016). Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. -

Computational scores

Source: dbNSFP v4.3

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: rs1203886148; hg19: chr22-50964231;