Genetic Variant TYMS:c.205+117G>C (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 NM_001071.4(TYMS):c.205+117G>C variant causes a intron 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

TYMS
NM_001071.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.407

Variant links:

Genes affected

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:

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

TYMSOS links:

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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
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
TYMSOS	NR_171001.1 link	n.228C>G	non_coding_transcript_exon_variant	Exon 1 of 2

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

Gnomad4 AFR exome

AF:

0.377

AC:

12186

AN:

32358

Gnomad4 AMR exome

AF:

0.215

AC:

8499

AN:

39560

Gnomad4 ASJ exome

AF:

0.186

AC:

4723

AN:

25336

Gnomad4 EAS exome

AF:

0.519

AC:

19342

AN:

37236

Gnomad4 SAS exome

AF:

0.322

AC:

26062

AN:

80980

Gnomad4 FIN exome

AF:

0.103

AC:

4727

AN:

46012

Gnomad4 NFE exome

AF:

0.132

AC:

144322

AN:

1093726

Gnomad4 Remaining exome

AF:

0.201

AC:

11817

AN:

58910

Heterozygous variant carriers

10075

20151

30226

40302

50377

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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

Gnomad4 AFR

AF:

0.367

AC:

0.367269

AN:

0.367269

Gnomad4 AMR

AF:

0.197

AC:

0.19677

AN:

0.19677

Gnomad4 ASJ

AF:

0.190

AC:

0.19049

AN:

0.19049

Gnomad4 EAS

AF:

0.529

AC:

0.528756

AN:

0.528756

Gnomad4 SAS

AF:

0.330

AC:

0.330012

AN:

0.330012

Gnomad4 FIN

AF:

0.100

AC:

0.100189

AN:

0.100189

Gnomad4 NFE

AF:

0.132

AC:

0.132365

AN:

0.132365

Gnomad4 OTH

AF:

0.218

AC:

0.217597

AN:

0.217597

Heterozygous variant carriers

1260

2520

3780

5040

6300

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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

DANN

Benign

0.48

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over