Genetic Variant TYMP:p.Glu38Lys (chr22-50529598-C-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1PM2

The NM_001953.5(TYMP):c.112G>A(p.Glu38Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,728 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. E38G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TYMP
NM_001953.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.54

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:

CIMAP1B (HGNC:34388): (ciliary microtubule associated protein 1B) Predicted to be active in cytoskeleton. [provided by Alliance of Genome Resources, Apr 2022]

CIMAP1B links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_001953.5

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TYMP	NM_001953.5 link	c.112G>A	p.Glu38Lys	missense_variant	Exon 2 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.112G>A	p.Glu38Lys	missense_variant	Exon 2 of 10	1	NM_001953.5	ENSP00000252029.3		P19971-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460728

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726712

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33472

American (AMR)

AF:

0.00

AC:

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26110

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.00

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52502

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111864

Other (OTH)

AF:

0.00

AC:

AN:

60370

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

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.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Uncertain

0.091

BayesDel_noAF

Benign

-0.11

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.63

D;.;D;D;T

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Benign

0.68

LIST_S2

Benign

0.64

.;T;.;T;T

M_CAP

Pathogenic

0.38

MetaRNN

Uncertain

0.56

D;D;D;D;D

MetaSVM

Pathogenic

0.86

MutationAssessor

Uncertain

2.8

M;M;M;M;.

PhyloP100

3.5

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-2.8

D;D;D;D;D

REVEL

Uncertain

0.52

Sift

Benign

0.057

T;D;T;T;D

Sift4G

Uncertain

0.042

D;D;D;D;T

Polyphen

0.96

D;.;D;D;.

Vest4

0.42

MutPred

0.55

Gain of MoRF binding (P = 0.0106);Gain of MoRF binding (P = 0.0106);Gain of MoRF binding (P = 0.0106);Gain of MoRF binding (P = 0.0106);Gain of MoRF binding (P = 0.0106);

MVP

0.91

MPC

0.54

ClinPred

0.97

GERP RS

5.2

PromoterAI

-0.037

Neutral

(source)

Varity_R

0.55

gMVP

0.85

Mutation Taster

=45/55

disease causing

(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

Computational scores

Splicing

Publications

Other links and lift over