Genetic Variant NM_001953.5:c.146T>A (chr22-50529564-A-T) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_Strong

The NM_001953.5(TYMP):c.146T>A(p.Leu49Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,264 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. L49R) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Consequence

TYMP
NM_001953.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.42

Publications

1 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: Pathogenic. The variant received 10 ACMG points.

PM1

In a hotspot region, there are 3 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;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr22-50529564-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 223017.Status of the report is no_assertion_criteria_provided, 0 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.988

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TYMP	NM_001953.5 link	c.146T>A	p.Leu49Gln	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.146T>A	p.Leu49Gln	missense_variant	Exon 2 of 10	1	NM_001953.5	ENSP00000252029.3		P19971-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152264

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152264

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74394

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41476

American (AMR)

AF:

0.00

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.75

BayesDel_addAF

Pathogenic

0.54

BayesDel_noAF

Pathogenic

0.54

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.94

D;.;D;D;D

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.93

.;D;.;D;D

M_CAP

Pathogenic

0.82

MetaRNN

Pathogenic

0.99

D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.0

H;H;H;H;.

PhyloP100

3.4

PrimateAI

Uncertain

0.60

PROVEAN

Pathogenic

-5.3

D;D;D;D;D

REVEL

Pathogenic

0.93

Sift

Uncertain

0.0010

D;D;D;D;D

Sift4G

Uncertain

0.0050

D;D;D;D;D

Polyphen

1.0

D;.;D;D;.

Vest4

0.77

MutPred

0.85

Gain of disorder (P = 0.0351);Gain of disorder (P = 0.0351);Gain of disorder (P = 0.0351);Gain of disorder (P = 0.0351);Gain of disorder (P = 0.0351);

MVP

0.97

MPC

1.3

ClinPred

1.0

GERP RS

4.8

PromoterAI

-0.029

Neutral

(source)

Varity_R

0.98

gMVP

1.0

Mutation Taster

=22/78

disease causing

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over