22-50525807-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001953.5(TYMP):c.1412C>T(p.Ser471Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0995 in 1,610,390 control chromosomes in the GnomAD database, including 9,556 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S471S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.090 ( 778 hom., cov: 35)

Exomes 𝑓: 0.10 ( 8778 hom. )

Consequence

TYMP
NM_001953.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: 1.14

Publications

52 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0021177828).

BP6

Variant 22-50525807-G-A is Benign according to our data. Variant chr22-50525807-G-A is described in ClinVar as Benign. ClinVar VariationId is 130693.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.241 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TYMP	NM_001953.5 link	c.1412C>T	p.Ser471Leu	missense_variant	Exon 10 of 10	ENST00000252029.8	NP_001944.1	P19971-1E5KRG5
SCO2	NM_005138.3 link	c.-349C>T		upstream_gene_variant		ENST00000395693.8	NP_005129.2	O43819

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TYMP	ENST00000252029.8 link	c.1412C>T	p.Ser471Leu	missense_variant	Exon 10 of 10	1	NM_001953.5	ENSP00000252029.3		P19971-1
SCO2	ENST00000395693.8 link	c.-349C>T		upstream_gene_variant		1	NM_005138.3	ENSP00000379046.4		O43819

Frequencies

GnomAD3 genomes

AF:

0.0899

AC:

13689

AN:

152208

Hom.:

778

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0507

Gnomad AMI

AF:

0.0164

Gnomad AMR

AF:

0.133

Gnomad ASJ

AF:

0.0697

Gnomad EAS

AF:

0.253

Gnomad SAS

AF:

0.191

Gnomad FIN

AF:

0.0908

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0866

Gnomad OTH

AF:

0.0969

GnomAD2 exomes

AF:

0.128

AC:

29384

AN:

230034

AF XY:

0.125

show subpopulations

Gnomad AFR exome

AF:

0.0493

Gnomad AMR exome

AF:

0.207

Gnomad ASJ exome

AF:

0.0688

Gnomad EAS exome

AF:

0.258

Gnomad FIN exome

AF:

0.0933

Gnomad NFE exome

AF:

0.0885

Gnomad OTH exome

AF:

0.103

GnomAD4 exome

AF:

0.100

AC:

146515

AN:

1458068

Hom.:

8778

Cov.:

AF XY:

0.102

AC XY:

74188

AN XY:

725332

show subpopulations

African (AFR)

AF:

0.0482

AC:

1609

AN:

33392

American (AMR)

AF:

0.195

AC:

8676

AN:

44494

Ashkenazi Jewish (ASJ)

AF:

0.0685

AC:

1785

AN:

26060

East Asian (EAS)

AF:

0.240

AC:

9502

AN:

39612

South Asian (SAS)

AF:

0.172

AC:

14851

AN:

86168

European-Finnish (FIN)

AF:

0.0947

AC:

4889

AN:

51608

Middle Eastern (MID)

AF:

0.0638

AC:

365

AN:

5722

European-Non Finnish (NFE)

AF:

0.0885

AC:

98278

AN:

1110890

Other (OTH)

AF:

0.109

AC:

6560

AN:

60122

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

7959

15918

23877

31836

39795

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3834

7668

11502

15336

19170

<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

AF:

0.0899

AC:

13695

AN:

152322

Hom.:

778

Cov.:

AF XY:

0.0928

AC XY:

6912

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.0506

AC:

2103

AN:

41586

American (AMR)

AF:

0.133

AC:

2037

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0697

AC:

242

AN:

3470

East Asian (EAS)

AF:

0.253

AC:

1310

AN:

5186

South Asian (SAS)

AF:

0.191

AC:

925

AN:

4832

European-Finnish (FIN)

AF:

0.0908

AC:

964

AN:

10618

Middle Eastern (MID)

AF:

0.0171

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0866

AC:

5889

AN:

68004

Other (OTH)

AF:

0.0969

AC:

205

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

674

1349

2023

2698

3372

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

162

324

486

648

810

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0890

Hom.:

849

Bravo

AF:

0.0900

TwinsUK

AF:

0.0823

AC:

305

ALSPAC

AF:

0.0924

AC:

356

ESP6500AA

AF:

0.0440

AC:

183

ESP6500EA

AF:

0.0807

AC:

663

ExAC

AF:

0.120

AC:

14146

Asia WGS

AF:

0.229

AC:

793

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Jul 10, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 23, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:4

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 07, 2011

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Mitochondrial DNA depletion syndrome 1

Benign:3

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jul 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 14, 2016

GeneReviews

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Spinal muscular atrophy

Benign:1

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Fatal Infantile Cardioencephalomyopathy

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.13

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.20

T;.;T;T;T

Eigen

Benign

-0.69

Eigen_PC

Benign

-0.72

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.67

.;T;.;T;T

MetaRNN

Benign

0.0021

T;T;T;T;T

MetaSVM

Benign

-0.66

MutationAssessor

Benign

1.7

L;.;L;L;.

PhyloP100

1.1

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-0.61

N;N;N;N;N

REVEL

Uncertain

0.32

Sift

Benign

0.40

T;T;T;T;T

Sift4G

Benign

0.33

T;T;T;T;T

Polyphen

0.99

D;.;D;D;.

Vest4

0.28

MPC

0.92

ClinPred

0.033

GERP RS

2.2

PromoterAI

0.049

Neutral

(source)

Varity_R

0.14

gMVP

0.56

Mutation Taster

=86/14

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over