Genetic Variant TYMSOS:n.511+196_511+197insCGGGACGGAGGCAGGCCAAGTGGCGCGG (chr18-657645-A-ACCGCGCCACTTGGCCTGCCTCCGTCCCG) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1BS2

The ENST00000323813.6(TYMSOS):n.511+196_511+197insCGGGACGGAGGCAGGCCAAGTGGCGCGG variant causes a intron change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0078 ( 39 hom., cov: 0)

Exomes 𝑓: 0.00047 ( 3 hom. )

Consequence

TYMSOS
ENST00000323813.6 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.618

Publications

51 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:

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ACMG classification

Classification was made for transcript

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

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00776 (1151/148296) while in subpopulation AFR AF = 0.0264 (1053/39892). AF 95% confidence interval is 0.0251. There are 39 homozygotes in GnomAd4. There are 507 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 39 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
TYMSOS	NR_171001.1 link	n.450+169_450+196dupCGGGACGGAGGCAGGCCAAGTGGCGCGG	intron_variant	Intron 1 of 1
TYMS	NM_001071.4 link	c.-98_-97insCCGCGCCACTTGGCCTGCCTCCGTCCCG	upstream_gene_variant		ENST00000323274.15	NP_001062.1	P04818-1Q53Y97
TYMS	NM_001354867.2 link	c.-98_-97insCCGCGCCACTTGGCCTGCCTCCGTCCCG	upstream_gene_variant			NP_001341796.1
TYMS	NM_001354868.2 link	c.-98_-97insCCGCGCCACTTGGCCTGCCTCCGTCCCG	upstream_gene_variant			NP_001341797.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TYMS	ENST00000323274.15 link	c.-98_-97insCCGCGCCACTTGGCCTGCCTCCGTCCCG		upstream_gene_variant		1	NM_001071.4	ENSP00000315644.10		P04818-1

Frequencies

GnomAD3 genomes

AF:

0.00777

AC:

1152

AN:

148190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0265

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00280

Gnomad ASJ

AF:

0.00116

Gnomad EAS

AF:

0.000797

Gnomad SAS

AF:

0.00149

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000449

Gnomad OTH

AF:

0.00592

GnomAD4 exome

AF:

0.000472

AC:

403

AN:

854572

Hom.:

Cov.:

AF XY:

0.000478

AC XY:

201

AN XY:

420306

show subpopulations

African (AFR)

AF:

0.0107

AC:

173

AN:

16226

American (AMR)

AF:

0.00267

AC:

AN:

7494

Ashkenazi Jewish (ASJ)

AF:

0.00162

AC:

AN:

12938

East Asian (EAS)

AF:

0.000724

AC:

AN:

22104

South Asian (SAS)

AF:

0.000855

AC:

AN:

28070

European-Finnish (FIN)

AF:

0.000201

AC:

AN:

24826

Middle Eastern (MID)

AF:

0.000790

AC:

AN:

2532

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

704788

Other (OTH)

AF:

0.00138

AC:

AN:

35594

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.429

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.00776

AC:

1151

AN:

148296

Hom.:

Cov.:

AF XY:

0.00700

AC XY:

507

AN XY:

72388

show subpopulations

African (AFR)

AF:

0.0264

AC:

1053

AN:

39892

American (AMR)

AF:

0.00280

AC:

AN:

15012

Ashkenazi Jewish (ASJ)

AF:

0.00116

AC:

AN:

3444

East Asian (EAS)

AF:

0.000800

AC:

AN:

5002

South Asian (SAS)

AF:

0.00128

AC:

AN:

4704

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10252

Middle Eastern (MID)

AF:

0.00

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.000449

AC:

AN:

66760

Other (OTH)

AF:

0.00585

AC:

AN:

2050

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

118

158

197

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.000105

Hom.:

531

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.62

Mutation Taster

=300/0

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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18-657645-ACCGCGCCACTTGGCCTGCCTCCGTCCCGCCGCGCCACTTGGCCTGCCTCCGTCCCG-ACCGCGCCACTTGGCCTGCCTCCGTCCCGCCGCGCCACTTGGCCTGCCTCCGTCCCGCCGCGCCACTTGGCCTGCCTCCGTCCCG

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