dbSNP rs764275775: TYMP:p.Ala454Ser (chr22-50525859-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM2PM5BP4_Moderate

The NM_001953.5(TYMP):c.1360G>T(p.Ala454Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A454P) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TYMP
NM_001953.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0100

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]

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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr22-50525859-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 223057.Status of the report is no_assertion_criteria_provided, 0 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.19026965).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TYMP	NM_001953.5 link	c.1360G>T	p.Ala454Ser	missense_variant	Exon 10 of 10	ENST00000252029.8	NP_001944.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TYMP	ENST00000252029.8 link	c.1360G>T	p.Ala454Ser	missense_variant	Exon 10 of 10	1	NM_001953.5	ENSP00000252029.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1447908

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

719532

African (AFR)

AF:

0.00

AC:

AN:

32884

American (AMR)

AF:

0.00

AC:

AN:

42944

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25832

East Asian (EAS)

AF:

0.00

AC:

AN:

39098

South Asian (SAS)

AF:

0.00

AC:

AN:

85330

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50666

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5412

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1106146

Other (OTH)

AF:

0.00

AC:

AN:

59596

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000881

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.081

BayesDel_noAF

Benign

-0.35

CADD

Benign

7.5

(source)

DANN

Benign

0.66

DEOGEN2

Benign

0.15

T;.;T;T;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.38

.;T;.;T;T

M_CAP

Pathogenic

0.79

MetaRNN

Benign

0.19

T;T;T;T;T

MetaSVM

Benign

-0.83

MutationAssessor

Benign

1.7

L;.;L;L;.

PhyloP100

-0.010

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-0.080

N;N;N;N;N

REVEL

Benign

0.16

Sift

Benign

0.50

T;T;T;T;T

Sift4G

Benign

0.41

T;T;T;T;T

Polyphen

0.016

B;.;B;B;.

Vest4

0.39

MutPred

0.37

Gain of phosphorylation at A454 (P = 0.0374);.;Gain of phosphorylation at A454 (P = 0.0374);Gain of phosphorylation at A454 (P = 0.0374);.;

MVP

0.43

MPC

0.41

ClinPred

0.048

GERP RS

1.0

PromoterAI

-0.034

Neutral

(source)

Varity_R

0.18

gMVP

0.35

Mutation Taster

=71/29

polymorphism

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over