dbSNP rs73366471: TYMSOS:n.352C>T (chr18-658001-G-A) – ACMG Classification: Benign (-7 pts)

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 1P and 8B. PP3BS1BS2

The ENST00000323813.6(TYMSOS):n.352C>T 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 0.00274 in 1,521,696 control chromosomes in the GnomAD database, including 115 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.014 ( 54 hom., cov: 32)

Exomes 𝑓: 0.0015 ( 61 hom. )

Consequence

TYMSOS
ENST00000323813.6 non_coding_transcript_exon

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.307

Publications

8 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 -7 ACMG points.

PP3

BayesDel_noAF computational evidence supports a deleterious effect, 0.15

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0138 (2103/152320) while in subpopulation AFR AF = 0.0465 (1933/41576). AF 95% confidence interval is 0.0448. There are 54 homozygotes in GnomAd4. There are 1033 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 54 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
TYMS	NM_001071.4 link	c.205+54G>A	intron_variant	Intron 1 of 6	ENST00000323274.15	NP_001062.1	P04818-1Q53Y97
TYMSOS	NR_171001.1 link	n.291C>T	non_coding_transcript_exon_variant	Exon 1 of 2
TYMS	NM_001354867.2 link	c.205+54G>A	intron_variant	Intron 1 of 5		NP_001341796.1
TYMS	NM_001354868.2 link	c.205+54G>A	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+54G>A		intron_variant	Intron 1 of 6	1	NM_001071.4	ENSP00000315644.10		P04818-1

Frequencies

GnomAD3 genomes

AF:

0.0137

AC:

2084

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0462

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00739

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000367

Gnomad OTH

AF:

0.0134

GnomAD2 exomes

AF:

0.00378

AC:

516

AN:

136342

AF XY:

0.00293

show subpopulations

Gnomad AFR exome

AF:

0.0494

Gnomad AMR exome

AF:

0.00397

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000207

Gnomad OTH exome

AF:

0.00215

GnomAD4 exome

AF:

0.00151

AC:

2074

AN:

1369376

Hom.:

Cov.:

AF XY:

0.00134

AC XY:

905

AN XY:

672982

show subpopulations

African (AFR)

AF:

0.0489

AC:

1500

AN:

30646

American (AMR)

AF:

0.00414

AC:

133

AN:

32094

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22332

East Asian (EAS)

AF:

0.00

AC:

AN:

36058

South Asian (SAS)

AF:

0.000163

AC:

AN:

73564

European-Finnish (FIN)

AF:

0.00

AC:

AN:

44072

Middle Eastern (MID)

AF:

0.00582

AC:

AN:

5498

European-Non Finnish (NFE)

AF:

0.000160

AC:

171

AN:

1068440

Other (OTH)

AF:

0.00399

AC:

226

AN:

56672

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

109

218

328

437

546

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

168

224

280

<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:

0.0138

AC:

2103

AN:

152320

Hom.:

Cov.:

AF XY:

0.0139

AC XY:

1033

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.0465

AC:

1933

AN:

41576

American (AMR)

AF:

0.00738

AC:

113

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.000207

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000368

AC:

AN:

68024

Other (OTH)

AF:

0.0133

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

105

210

315

420

525

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<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:

0.00310

Hom.:

Bravo

AF:

0.0155

Asia WGS

AF:

0.00260

AC:

AN:

3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Pathogenic

0.15

CADD

Benign

9.0

(source)

DANN

Benign

0.97

PhyloP100

-0.31

PromoterAI

0.015

Neutral

(source)

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.0

Mutation Taster

=200/0

disease causing (fs/PTC)

(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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over