22-50525778-G-A

Position:

chr22-50525778-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_ModeratePM2

The NM_001953.5(TYMP):c.1441C>T(p.Gln481*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000238 in 1,610,684 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 (★★).

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 35)

Exomes 𝑓: 0.00025 ( 0 hom. )

Consequence

TYMP
NM_001953.5 stop_gained

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: -1.29

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:

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]

SCO2 links:

TYMP (HGNC:):

TYMP links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 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 0.00552 CDS is truncated, and there are 0 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TYMP	NM_001953.5 linkuse as main transcript	c.1441C>T	p.Gln481*	stop_gained	10/10	ENST00000252029.8	NP_001944.1	P19971-1E5KRG5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TYMP	ENST00000252029.8 linkuse as main transcript	c.1441C>T	p.Gln481*	stop_gained	10/10	1	NM_001953.5	ENSP00000252029.3		P19971-1

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152254

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

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:

0.000176

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000559

AC:

AN:

232468

Hom.:

AF XY:

0.0000543

AC XY:

AN XY:

128904

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000662

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000987

Gnomad OTH exome

AF:

0.000175

GnomAD4 exome

AF:

0.000253

AC:

369

AN:

1458430

Hom.:

Cov.:

AF XY:

0.000254

AC XY:

184

AN XY:

725524

show subpopulations

Gnomad4 AFR exome

AF:

0.0000599

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000812

Gnomad4 FIN exome

AF:

0.0000193

Gnomad4 NFE exome

AF:

0.000317

Gnomad4 OTH exome

AF:

0.0000997

GnomAD4 genome

AF:

0.0000920

AC:

AN:

152254

Hom.:

Cov.:

AF XY:

0.0000941

AC XY:

AN XY:

74386

show subpopulations

Gnomad4 AFR

AF:

0.0000482

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:

0.000176

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000161

Hom.:

Bravo

AF:

0.0000756

ESP6500AA

AF:

0.000238

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000589

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Dec 12, 2023

Variant summary: TYMP c.1441C>T (p.Gln481X) results in a premature termination codon, predicted to cause a truncation of the last two amino acids of the protein and not expected to result in nonsense mediated decay. The variant allele was found at a frequency of 5.6e-05 in 232468 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in TYMP causing Mitochondrial DNA Depletion Syndrome 1 (MNGIE type) (5.6e-05 vs 0.0011), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.1441C>T in individuals affected with Mitochondrial DNA Depletion Syndrome 1 (MNGIE type) and no experimental evidence demonstrating its impact on protein function have been reported. Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Mitochondrial DNA depletion syndrome 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Aug 01, 2017

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 29, 2022

This sequence change creates a premature translational stop signal (p.Gln481*) in the TYMP gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 2 amino acid(s) of the TYMP protein. This variant is present in population databases (rs200735968, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with TYMP-related conditions. ClinVar contains an entry for this variant (Variation ID: 553052). 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. -

TYMP-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 10, 2023

The TYMP c.1441C>T variant is predicted to result in premature protein termination (p.Gln481*). To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.012% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/22-50964207-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.33

CADD

Pathogenic

DANN

Benign

0.95

Eigen

Benign

-0.058

Eigen_PC

Benign

-0.52

FATHMM_MKL

Benign

0.55

MutationTaster

Benign

1.0

N;N;N;N;N;N

Vest4

0.40

GERP RS

-0.34

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

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