18-658147-C-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001071.4(TYMS):c.205+200C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00994 in 1,583,902 control chromosomes in the GnomAD database, including 92 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0079 (4 hom., cov: 33)
  • Exomes 𝑓: 0.010 (88 hom.)
• Consequence: TYMS NM_001071.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.722

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]

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

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 18-658147-C-A is Benign according to our data. Variant chr18-658147-C-A is described in ClinVar as [Benign]. Clinvar id is 2648512.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 4 Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TYMS	NM_001071.4	c.205+200C>A		intron_variant		ENST00000323274.15
TYMSOS	NR_171001.1	n.145G>T		non_coding_transcript_exon_variant	1/2
TYMS	NM_001354867.2	c.205+200C>A		intron_variant
TYMS	NM_001354868.2	c.205+200C>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TYMS	ENST00000323274.15	c.205+200C>A		intron_variant		1	NM_001071.4	P1
TYMSOS	ENST00000585033.1	n.123G>T		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes AF: 0.00787 AC: 1196 AN: 151932 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.00225

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.0120

Gnomad ASJ AF: 0.0170

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00270

Gnomad FIN AF: 0.00217

Gnomad MID AF: 0.00968

Gnomad NFE AF: 0.0115

Gnomad OTH AF: 0.0120

GnomAD3 exomes AF: 0.00751 AC: 1546 AN: 205736 Hom.: 14 AF XY: 0.00748 AC XY: 851 AN XY: 113728

Gnomad AFR exome AF: 0.00195

Gnomad AMR exome AF: 0.00787

Gnomad ASJ exome AF: 0.0184

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00253

Gnomad FIN exome AF: 0.00161

Gnomad NFE exome AF: 0.0105

Gnomad OTH exome AF: 0.0108

GnomAD4 exome AF: 0.0102 AC: 14546 AN: 1431848 Hom.: 88 Cov.: 32 AF XY: 0.0100 AC XY: 7126 AN XY: 711104

Gnomad4 AFR exome AF: 0.00186

Gnomad4 AMR exome AF: 0.00810

Gnomad4 ASJ exome AF: 0.0176

Gnomad4 EAS exome AF: 0.0000262

Gnomad4 SAS exome AF: 0.00241

Gnomad4 FIN exome AF: 0.00249

Gnomad4 NFE exome AF: 0.0116

Gnomad4 OTH exome AF: 0.00983

GnomAD4 genome AF: 0.00786 AC: 1195 AN: 152054 Hom.: 4 Cov.: 33 AF XY: 0.00749 AC XY: 557 AN XY: 74370

Gnomad4 AFR AF: 0.00224

Gnomad4 AMR AF: 0.0120

Gnomad4 ASJ AF: 0.0170

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00270

Gnomad4 FIN AF: 0.00217

Gnomad4 NFE AF: 0.0115

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.0113 Hom.: 6

Bravo AF: 0.00818

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Mar 01, 2023

TYMSOS: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
Cadd	Benign	3.7
Dann	Benign	0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs182344736; hg19: chr18-658147; COSMIC: COSV105176282; COSMIC: COSV105176282;