NM_001953.5:c.1393G>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.1393G>A(p.Ala465Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0498 in 1,609,694 control chromosomes in the GnomAD database, including 2,263 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A465S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.039 ( 145 hom., cov: 34)

Exomes 𝑓: 0.051 ( 2118 hom. )

Consequence

TYMP
NM_001953.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: -0.495

Publications

27 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=0.0017577708).

BP6

Variant 22-50525826-C-T is Benign according to our data. Variant chr22-50525826-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 137878.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0528 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TYMP	NM_001953.5 link	c.1393G>A	p.Ala465Thr	missense_variant	Exon 10 of 10	ENST00000252029.8	NP_001944.1	P19971-1E5KRG5
SCO2	NM_005138.3 link	c.-368G>A		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.1393G>A	p.Ala465Thr	missense_variant	Exon 10 of 10	1	NM_001953.5	ENSP00000252029.3		P19971-1
SCO2	ENST00000395693.8 link	c.-368G>A		upstream_gene_variant		1	NM_005138.3	ENSP00000379046.4		O43819

Frequencies

GnomAD3 genomes

AF:

0.0395

AC:

6011

AN:

152196

Hom.:

145

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0107

Gnomad AMI

AF:

0.0482

Gnomad AMR

AF:

0.0345

Gnomad ASJ

AF:

0.0885

Gnomad EAS

AF:

0.000770

Gnomad SAS

AF:

0.0513

Gnomad FIN

AF:

0.0588

Gnomad MID

AF:

0.127

Gnomad NFE

AF:

0.0542

Gnomad OTH

AF:

0.0406

GnomAD2 exomes

AF:

0.0459

AC:

10439

AN:

227524

AF XY:

0.0483

show subpopulations

Gnomad AFR exome

AF:

0.00963

Gnomad AMR exome

AF:

0.0275

Gnomad ASJ exome

AF:

0.0855

Gnomad EAS exome

AF:

0.000172

Gnomad FIN exome

AF:

0.0584

Gnomad NFE exome

AF:

0.0541

Gnomad OTH exome

AF:

0.0544

GnomAD4 exome

AF:

0.0508

AC:

74101

AN:

1457384

Hom.:

2118

Cov.:

AF XY:

0.0518

AC XY:

37532

AN XY:

724990

show subpopulations

African (AFR)

AF:

0.00980

AC:

327

AN:

33374

American (AMR)

AF:

0.0289

AC:

1287

AN:

44476

Ashkenazi Jewish (ASJ)

AF:

0.0872

AC:

2270

AN:

26040

East Asian (EAS)

AF:

0.000177

AC:

AN:

39578

South Asian (SAS)

AF:

0.0600

AC:

5169

AN:

86118

European-Finnish (FIN)

AF:

0.0584

AC:

3006

AN:

51480

Middle Eastern (MID)

AF:

0.103

AC:

583

AN:

5666

European-Non Finnish (NFE)

AF:

0.0527

AC:

58488

AN:

1110558

Other (OTH)

AF:

0.0493

AC:

2964

AN:

60094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

4058

8115

12173

16230

20288

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2162

4324

6486

8648

10810

<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:

0.0395

AC:

6012

AN:

152310

Hom.:

145

Cov.:

AF XY:

0.0403

AC XY:

3002

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.0107

AC:

443

AN:

41576

American (AMR)

AF:

0.0344

AC:

527

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0885

AC:

307

AN:

3470

East Asian (EAS)

AF:

0.000772

AC:

AN:

5180

South Asian (SAS)

AF:

0.0519

AC:

251

AN:

4834

European-Finnish (FIN)

AF:

0.0588

AC:

624

AN:

10616

Middle Eastern (MID)

AF:

0.130

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0542

AC:

3689

AN:

68008

Other (OTH)

AF:

0.0402

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

322

645

967

1290

1612

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

152

228

304

380

<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:

0.0424

Hom.:

101

Bravo

AF:

0.0364

TwinsUK

AF:

0.0585

AC:

217

ALSPAC

AF:

0.0457

AC:

176

ESP6500AA

AF:

0.0114

AC:

ESP6500EA

AF:

0.0513

AC:

417

ExAC

AF:

0.0441

AC:

5184

Asia WGS

AF:

0.0210

AC:

AN:

3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

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

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 23, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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. -

Mar 06, 2017

Counsyl

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Jul 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Jul 18, 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. -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mitochondrial neurogastrointestinal encephalomyopathy

Benign:1

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

TYMP-related disorder

Benign:1

Apr 01, 2021

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Fatal Infantile Cardioencephalomyopathy

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.41

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.16

T;.;T;T;T

Eigen

Benign

-0.78

Eigen_PC

Benign

-0.75

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.54

.;T;.;T;T

MetaRNN

Benign

0.0018

T;T;T;T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.8

L;.;L;L;.

PhyloP100

-0.49

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-0.14

N;N;N;N;N

REVEL

Benign

0.23

Sift

Benign

0.24

T;T;T;T;T

Sift4G

Benign

0.31

T;T;T;T;T

Polyphen

0.14

B;.;B;B;.

Vest4

0.055

MPC

0.45

ClinPred

0.014

GERP RS

2.3

PromoterAI

0.040

Neutral

(source)

Varity_R

0.17

gMVP

0.34

Mutation Taster

=100/0

polymorphism (auto)

(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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over