chr22-50529213-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_001953.5(TYMP):c.340G>A(p.Asp114Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000616 in 1,460,938 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D114E) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

TYMP
NM_001953.5 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 3.73

Publications

4 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 Gene-Disease associations (from GenCC):

mitochondrial disease
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
mitochondrial DNA depletion syndrome 1
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
mitochondrial neurogastrointestinal encephalomyopathy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

TYMP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_001953.5

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr22-50529211-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3897055.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.987

PP5

Variant 22-50529213-C-T is Pathogenic according to our data. Variant chr22-50529213-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 223024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TYMP	NM_001953.5 link	c.340G>A	p.Asp114Asn	missense_variant	Exon 3 of 10	ENST00000252029.8	NP_001944.1	P19971-1E5KRG5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TYMP	ENST00000252029.8 link	c.340G>A	p.Asp114Asn	missense_variant	Exon 3 of 10	1	NM_001953.5	ENSP00000252029.3		P19971-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000799

AC:

AN:

250418

AF XY:

0.0000147

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:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1460938

Hom.:

Cov.:

AF XY:

0.00000826

AC XY:

AN XY:

726784

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52494

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000809

AC:

AN:

1111994

Other (OTH)

AF:

0.00

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

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

Cov.:

Alfa

AF:

0.0000565

Hom.:

Bravo

AF:

0.0000113

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Mitochondrial DNA depletion syndrome 1

Pathogenic:3

Sep 13, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: TYMP c.340G>A (p.Asp114Asn) results in a conservative amino acid change located in the Glycosyl transferase, family 3 domain (IPR000312) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250418 control chromosomes. c.340G>A has been reported in the literature in homozygous or compound heterozygous individuals affected with Mitochondrial DNA Depletion Syndrome 1 (MNGIE type) (Slama_2005, Zimmer_2020). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 15781193, 19368660). ClinVar contains an entry for this variant (Variation ID: 223024). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Jan 31, 2023

Baylor Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 14, 2016

GeneReviews

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Pathogenic

0.16

BayesDel_noAF

Uncertain

0.010

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.98

D;.;D;D;D

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Uncertain

0.92

LIST_S2

Pathogenic

0.98

.;D;.;D;D

M_CAP

Pathogenic

0.46

MetaRNN

Pathogenic

0.99

D;D;D;D;D

MetaSVM

Pathogenic

0.95

MutationAssessor

Pathogenic

4.1

H;H;H;H;.

PhyloP100

3.7

PrimateAI

Uncertain

0.57

PROVEAN

Pathogenic

-4.9

D;D;D;D;D

REVEL

Pathogenic

0.80

Sift

Pathogenic

0.0

D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D

Polyphen

1.0

D;.;D;D;.

Vest4

0.90

MutPred

0.98

Gain of MoRF binding (P = 0.0638);Gain of MoRF binding (P = 0.0638);Gain of MoRF binding (P = 0.0638);Gain of MoRF binding (P = 0.0638);Gain of MoRF binding (P = 0.0638);

MVP

0.98

MPC

1.3

ClinPred

1.0

GERP RS

5.0

Varity_R

0.99

gMVP

0.98

Mutation Taster

=2/98

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over