Genetic Variant TYMSOS:n.289C>G (chr18-658064-G-C) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The ENST00000323813.6(TYMSOS):n.289C>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.17 in 1,571,972 control chromosomes in the GnomAD database, including 29,465 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.22 ( 4887 hom., cov: 33)

Exomes 𝑓: 0.16 ( 24578 hom. )

Consequence

TYMSOS
ENST00000323813.6 non_coding_transcript_exon

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.407

Publications

35 publications found

Variant links:

Genes affected

TYMSOS (HGNC:29553): (TYMS opposite strand RNA)

TYMSOS links:

TYMS (HGNC:12441): (thymidylate synthetase) Thymidylate synthase catalyzes the methylation of deoxyuridylate to deoxythymidylate using, 10-methylenetetrahydrofolate (methylene-THF) as a cofactor. This function maintains the dTMP (thymidine-5-prime monophosphate) pool critical for DNA replication and repair. The enzyme has been of interest as a target for cancer chemotherapeutic agents. It is considered to be the primary site of action for 5-fluorouracil, 5-fluoro-2-prime-deoxyuridine, and some folate analogs. Expression of this gene and that of a naturally occurring antisense transcript, mitochondrial enolase superfamily member 1 (GeneID:55556), vary inversely when cell-growth progresses from late-log to plateau phase. Polymorphisms in this gene may be associated with etiology of neoplasia, including breast cancer, and response to chemotherapy. [provided by RefSeq, Aug 2017]

TYMS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.512 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
TYMS	NM_001071.4 link	c.205+117G>C	intron_variant	Intron 1 of 6	ENST00000323274.15	NP_001062.1	P04818-1Q53Y97
TYMSOS	NR_171001.1 link	n.228C>G	non_coding_transcript_exon_variant	Exon 1 of 2
TYMS	NM_001354867.2 link	c.205+117G>C	intron_variant	Intron 1 of 5		NP_001341796.1
TYMS	NM_001354868.2 link	c.205+117G>C	intron_variant	Intron 1 of 4		NP_001341797.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TYMS	ENST00000323274.15 link	c.205+117G>C		intron_variant	Intron 1 of 6	1	NM_001071.4	ENSP00000315644.10		P04818-1

Frequencies

GnomAD3 genomes

AF:

0.222

AC:

33786

AN:

152004

Hom.:

4879

Cov.:

show subpopulations

Gnomad AFR

AF:

0.367

Gnomad AMI

AF:

0.0252

Gnomad AMR

AF:

0.197

Gnomad ASJ

AF:

0.190

Gnomad EAS

AF:

0.529

Gnomad SAS

AF:

0.330

Gnomad FIN

AF:

0.100

Gnomad MID

AF:

0.232

Gnomad NFE

AF:

0.132

Gnomad OTH

AF:

0.211

GnomAD2 exomes

AF:

0.219

AC:

40867

AN:

186736

AF XY:

0.219

show subpopulations

Gnomad AFR exome

AF:

0.369

Gnomad AMR exome

AF:

0.222

Gnomad ASJ exome

AF:

0.180

Gnomad EAS exome

AF:

0.535

Gnomad FIN exome

AF:

0.104

Gnomad NFE exome

AF:

0.135

Gnomad OTH exome

AF:

0.182

GnomAD4 exome

AF:

0.164

AC:

233180

AN:

1419848

Hom.:

24578

Cov.:

AF XY:

0.168

AC XY:

118098

AN XY:

703284

show subpopulations

African (AFR)

AF:

0.377

AC:

12186

AN:

32358

American (AMR)

AF:

0.215

AC:

8499

AN:

39560

Ashkenazi Jewish (ASJ)

AF:

0.186

AC:

4723

AN:

25336

East Asian (EAS)

AF:

0.519

AC:

19342

AN:

37236

South Asian (SAS)

AF:

0.322

AC:

26062

AN:

80980

European-Finnish (FIN)

AF:

0.103

AC:

4727

AN:

46012

Middle Eastern (MID)

AF:

0.262

AC:

1502

AN:

5730

European-Non Finnish (NFE)

AF:

0.132

AC:

144322

AN:

1093726

Other (OTH)

AF:

0.201

AC:

11817

AN:

58910

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

10075

20151

30226

40302

50377

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5734

11468

17202

22936

28670

<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:

0.222

AC:

33822

AN:

152124

Hom.:

4887

Cov.:

AF XY:

0.225

AC XY:

16705

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.367

AC:

15249

AN:

41520

American (AMR)

AF:

0.197

AC:

3009

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.190

AC:

661

AN:

3470

East Asian (EAS)

AF:

0.529

AC:

2703

AN:

5112

South Asian (SAS)

AF:

0.330

AC:

1590

AN:

4818

European-Finnish (FIN)

AF:

0.100

AC:

1062

AN:

10600

Middle Eastern (MID)

AF:

0.223

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.132

AC:

9000

AN:

67994

Other (OTH)

AF:

0.218

AC:

460

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1260

2520

3780

5040

6300

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

352

704

1056

1408

1760

<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:

0.158

Hom.:

774

Bravo

AF:

0.237

Asia WGS

AF:

0.428

AC:

1486

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.67

CADD

Benign

3.3

(source)

DANN

Benign

0.48

PhyloP100

0.41

PromoterAI

-0.0063

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.33

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.33

Position offset: 3

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over