GeneBe

rs786205097

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PVS1_StrongPM2PP5

The NM_001953.5(TYMP):​c.1410dupC​(p.Ser471LeufsTer19) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. P470P) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 34)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

TYMP
NM_001953.5 frameshift

Scores

Not classified

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: -0.869

Publications

0 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]
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

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 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. There are 5 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 22-50525808-A-AG is Pathogenic according to our data. Variant chr22-50525808-A-AG is described in ClinVar as Pathogenic. ClinVar VariationId is 16657.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001953.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
TYMP
NM_001953.5
MANE Select
c.1410dupCp.Ser471LeufsTer19
frameshift
Exon 10 of 10NP_001944.1
TYMP
NM_001257989.1
c.1425dupCp.Ser476LeufsTer19
frameshift
Exon 10 of 10NP_001244918.1
TYMP
NM_001113755.3
c.1410dupCp.Ser471LeufsTer19
frameshift
Exon 10 of 10NP_001107227.1

Ensembl Transcripts

Selected
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
TYMP
ENST00000252029.8
TSL:1 MANE Select
c.1410dupCp.Ser471LeufsTer19
frameshift
Exon 10 of 10ENSP00000252029.3
TYMP
ENST00000395681.6
TSL:1
c.1425dupCp.Ser476LeufsTer19
frameshift
Exon 10 of 10ENSP00000379038.1
TYMP
ENST00000395678.7
TSL:1
c.1410dupCp.Ser471LeufsTer18
frameshift
Exon 10 of 10ENSP00000379036.3

Frequencies

GnomAD3 genomes
Cov.:
34
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1458244
Hom.:
0
Cov.:
37
AF XY:
0.00
AC XY:
0
AN XY:
725440
African (AFR)
AF:
0.00
AC:
0
AN:
33384
American (AMR)
AF:
0.00
AC:
0
AN:
44590
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26058
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39614
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86178
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
51624
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5706
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1110962
Other (OTH)
AF:
0.00
AC:
0
AN:
60128
GnomAD4 genome
Cov.:
34

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic
Revision:no assertion criteria provided
View on ClinVar
Pathogenic
VUS
Benign
Condition
1
-
-
Mitochondrial DNA depletion syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name
Calibrated prediction
Score
Prediction
PhyloP100
-0.87
Mutation Taster
=3/197
disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs786205097; hg19: chr22-50964237; API