Genetic Variant TYMP:c.-46G>T (chr22-50529755-C-A) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_001113756.3(TYMP):c.-46G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000261 in 1,560,224 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0014 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00013 ( 2 hom. )

Consequence

TYMP
NM_001113756.3 5_prime_UTR_premature_start_codon_gain

Scores

Splicing: ADA: 0.00003153

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.806

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: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BP6

Variant 22-50529755-C-A is Benign according to our data. Variant chr22-50529755-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 379866.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00142 (217/152314) while in subpopulation AFR AF = 0.00488 (203/41572). AF 95% confidence interval is 0.00433. There are 1 homozygotes in GnomAd4. There are 103 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001113756.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TYMP	NM_001953.5	MANE Select	c.-10-36G>T	intron	N/A	NP_001944.1	E5KRG5
TYMP	NM_001113756.3		c.-46G>T	5_prime_UTR_premature_start_codon_gain	Exon 1 of 9	NP_001107228.1	E5KRG5
TYMP	NM_001113756.3		c.-46G>T	5_prime_UTR	Exon 1 of 9	NP_001107228.1	E5KRG5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TYMP	ENST00000487577.5	TSL:1	c.-46G>T	5_prime_UTR_premature_start_codon_gain	Exon 1 of 9	ENSP00000498844.1	P19971-1
TYMP	ENST00000487577.5	TSL:1	c.-46G>T	5_prime_UTR	Exon 1 of 9	ENSP00000498844.1	P19971-1
TYMP	ENST00000252029.8	TSL:1 MANE Select	c.-10-36G>T	intron	N/A	ENSP00000252029.3	P19971-1

Frequencies

GnomAD3 genomes

AF:

0.00143

AC:

217

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00490

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000523

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:

0.0000294

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.000324

AC:

AN:

185318

AF XY:

0.000295

show subpopulations

Gnomad AFR exome

AF:

0.00432

Gnomad AMR exome

AF:

0.000437

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000126

Gnomad OTH exome

AF:

0.000420

GnomAD4 exome

AF:

0.000135

AC:

190

AN:

1407910

Hom.:

Cov.:

AF XY:

0.000124

AC XY:

AN XY:

696096

show subpopulations

African (AFR)

AF:

0.00420

AC:

136

AN:

32348

American (AMR)

AF:

0.000439

AC:

AN:

38688

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25008

East Asian (EAS)

AF:

0.00

AC:

AN:

37880

South Asian (SAS)

AF:

0.0000123

AC:

AN:

81608

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48922

Middle Eastern (MID)

AF:

0.000692

AC:

AN:

4338

European-Non Finnish (NFE)

AF:

0.00000555

AC:

AN:

1081074

Other (OTH)

AF:

0.000465

AC:

AN:

58044

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

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:

0.00142

AC:

217

AN:

152314

Hom.:

Cov.:

AF XY:

0.00138

AC XY:

103

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.00488

AC:

203

AN:

41572

American (AMR)

AF:

0.000523

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68018

Other (OTH)

AF:

0.00189

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

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:

0.0000428

Hom.:

Bravo

AF:

0.00170

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

2.8

(source)

DANN

Benign

0.64

PhyloP100

-0.81

PromoterAI

-0.16

Neutral

(source)

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000032

dbscSNV1_RF

Benign

0.0

SpliceAI score (max)

0.14

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over