rs1060499533

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_001953.5(TYMP):c.1112T>C(p.Leu371Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000713 in 1,402,028 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 (★). Synonymous variant affecting the same amino acid position (i.e. L371L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

TYMP
NM_001953.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:1

Conservation

PhyloP100: 2.66

Publications

2 publications found

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 Gene-Disease associations (from GenCC):

cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
Leigh syndrome
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
myopia 6
Inheritance: AD Classification: STRONG Submitted by: G2P
autosomal recessive axonal charcot-marie-tooth disease due to copper metabolism defect
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

SCO2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.765

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TYMP	NM_001953.5 link	c.1112T>C	p.Leu371Pro	missense_variant	Exon 8 of 10	ENST00000252029.8	NP_001944.1	P19971-1E5KRG5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TYMP	ENST00000252029.8 link	c.1112T>C	p.Leu371Pro	missense_variant	Exon 8 of 10	1	NM_001953.5	ENSP00000252029.3		P19971-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

165974

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.13e-7

AC:

AN:

1402028

Hom.:

Cov.:

AF XY:

0.00000144

AC XY:

AN XY:

695232

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29650

American (AMR)

AF:

0.00

AC:

AN:

39874

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24900

East Asian (EAS)

AF:

0.00

AC:

AN:

35428

South Asian (SAS)

AF:

0.00

AC:

AN:

80670

European-Finnish (FIN)

AF:

0.00

AC:

AN:

35314

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5246

European-Non Finnish (NFE)

AF:

9.15e-7

AC:

AN:

1092642

Other (OTH)

AF:

0.00

AC:

AN:

58304

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Mitochondrial DNA depletion syndrome 1

Pathogenic:1

Jan 14, 2016

GeneReviews

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not provided

Uncertain:1

Nov 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 371 of the TYMP protein (p.Leu371Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with mitochondrial DNA depletion syndrome (PMID: 12529715). ClinVar contains an entry for this variant (Variation ID: 223052). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt TYMP protein function with a negative predictive value of 95%. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.39

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.55

D;.;D;D;T

Eigen

Benign

0.12

Eigen_PC

Benign

0.092

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.42

.;T;.;T;T

M_CAP

Pathogenic

0.89

MetaRNN

Pathogenic

0.76

D;D;D;D;D

MetaSVM

Uncertain

0.65

MutationAssessor

Uncertain

2.3

M;M;M;M;.

PhyloP100

2.7

PrimateAI

Pathogenic

0.87

PROVEAN

Uncertain

-2.5

D;D;D;D;N

REVEL

Pathogenic

0.74

Sift

Uncertain

0.0060

D;D;D;D;D

Sift4G

Benign

0.13

T;T;T;T;T

Polyphen

1.0

D;.;D;D;.

Vest4

0.67

MutPred

0.68

Loss of stability (P = 0.0881);Loss of stability (P = 0.0881);Loss of stability (P = 0.0881);Loss of stability (P = 0.0881);.;

MVP

0.88

MPC

1.6

ClinPred

0.97

GERP RS

3.3

PromoterAI

0.087

Neutral

(source)

Varity_R

0.90

gMVP

0.74

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over