Genetic Variant TYMP:p.Arg376Pro (chr22-50526278-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001953.5(TYMP):c.1127G>C(p.Arg376Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000718 in 1,392,852 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R376Q) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

TYMP
NM_001953.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.17

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.12140989).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TYMP	NM_001953.5 link	c.1127G>C	p.Arg376Pro	missense_variant	Exon 8 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.1127G>C	p.Arg376Pro	missense_variant	Exon 8 of 10	1	NM_001953.5	ENSP00000252029.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.18e-7

AC:

AN:

1392852

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

689804

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29368

American (AMR)

AF:

0.00

AC:

AN:

38268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24650

East Asian (EAS)

AF:

0.00

AC:

AN:

34746

South Asian (SAS)

AF:

0.00

AC:

AN:

79614

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34818

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5314

European-Non Finnish (NFE)

AF:

9.19e-7

AC:

AN:

1088076

Other (OTH)

AF:

0.00

AC:

AN:

57998

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.065

BayesDel_noAF

Benign

-0.33

CADD

Benign

4.7

(source)

DANN

Benign

0.78

DEOGEN2

Benign

0.19

T;.;T;T;T

Eigen

Benign

-1.9

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.29

LIST_S2

Benign

0.31

.;T;.;T;T

M_CAP

Pathogenic

0.81

MetaRNN

Benign

0.12

T;T;T;T;T

MetaSVM

Uncertain

0.0084

MutationAssessor

Benign

0.72

N;N;N;N;.

PhyloP100

-1.2

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-0.87

N;N;N;N;N

REVEL

Benign

0.17

Sift

Benign

0.26

T;T;T;T;T

Sift4G

Benign

0.48

T;T;T;T;T

Polyphen

0.0010

B;.;B;B;.

Vest4

0.17

MutPred

0.25

Gain of glycosylation at R376 (P = 0.0375);Gain of glycosylation at R376 (P = 0.0375);Gain of glycosylation at R376 (P = 0.0375);Gain of glycosylation at R376 (P = 0.0375);.;

MVP

0.35

MPC

0.64

ClinPred

0.075

GERP RS

-6.6

PromoterAI

-0.0052

Neutral

(source)

Varity_R

0.67

gMVP

0.50

Mutation Taster

=78/22

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