22-50526474-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PM5

The NM_001953.5(TYMP):c.931G>A(p.Gly311Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000302 in 1,491,022 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G311C) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

TYMP
NM_001953.5 missense, splice_region

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:2

Conservation

PhyloP100: 0.264

Publications

3 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), PanelApp Australia, G2P
Leigh syndrome
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
myopia 6
Inheritance: AD Classification: STRONG, NO_KNOWN Submitted by: G2P, PanelApp Australia
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 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr22-50526474-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 223049.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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TYMP	NM_001953.5	MANE Select	c.931G>A	p.Gly311Ser	missense splice_region	Exon 8 of 10	NP_001944.1	E5KRG5
TYMP	NM_001257989.1		c.931G>A	p.Gly311Ser	missense splice_region	Exon 8 of 10	NP_001244918.1	P19971-2
TYMP	NM_001113755.3		c.931G>A	p.Gly311Ser	missense splice_region	Exon 8 of 10	NP_001107227.1	E5KRG5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TYMP	ENST00000252029.8	TSL:1 MANE Select	c.931G>A	p.Gly311Ser	missense splice_region	Exon 8 of 10	ENSP00000252029.3	P19971-1
TYMP	ENST00000395681.6	TSL:1	c.931G>A	p.Gly311Ser	missense splice_region	Exon 8 of 10	ENSP00000379038.1	P19971-2
TYMP	ENST00000395678.7	TSL:1	c.931G>A	p.Gly311Ser	missense splice_region	Exon 8 of 10	ENSP00000379036.3	P19971-1

Frequencies

GnomAD3 genomes

AF:

0.0000395

AC:

AN:

151972

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000736

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000120

AC:

AN:

83282

AF XY:

0.0000216

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000317

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000291

AC:

AN:

1339050

Hom.:

Cov.:

AF XY:

0.0000334

AC XY:

AN XY:

658756

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27640

American (AMR)

AF:

0.00

AC:

AN:

28512

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21646

East Asian (EAS)

AF:

0.00

AC:

AN:

33518

South Asian (SAS)

AF:

0.0000139

AC:

AN:

71746

European-Finnish (FIN)

AF:

0.00

AC:

AN:

35552

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4082

European-Non Finnish (NFE)

AF:

0.0000321

AC:

AN:

1060706

Other (OTH)

AF:

0.0000719

AC:

AN:

55648

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000395

AC:

AN:

151972

Hom.:

Cov.:

AF XY:

0.0000674

AC XY:

AN XY:

74226

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41410

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10570

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.0000736

AC:

AN:

67938

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.542

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000136

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Mitochondrial DNA depletion syndrome 1 (2)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Uncertain

0.078

BayesDel_noAF

Uncertain

-0.020

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.72

Eigen

Benign

0.055

Eigen_PC

Benign

-0.096

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.78

M_CAP

Pathogenic

0.74

MetaRNN

Uncertain

0.74

MetaSVM

Pathogenic

0.95

MutationAssessor

Benign

1.4

PhyloP100

0.26

PrimateAI

Pathogenic

0.81

PROVEAN

Uncertain

-3.5

REVEL

Uncertain

0.59

Sift

Uncertain

0.017

Sift4G

Benign

0.095

Polyphen

1.0

Vest4

0.47

MutPred

0.64

Loss of catalytic residue at A312 (P = 0.287)

MVP

0.96

MPC

1.3

ClinPred

0.97

GERP RS

2.4

PromoterAI

-0.46

Neutral

(source)

Varity_R

0.78

gMVP

0.85

Mutation Taster

=21/79

disease causing (ClinVar)

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over