rs9952504

Variant names:

• chr18-657458-A-G
• rs9952504
• ENST00000323813.6:n.511+384T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000323813.6(TYMSOS):​n.511+384T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0772 in 261,410 control chromosomes in the GnomAD database, including 1,479 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 0.097 (1261 hom., cov: 31)
  • Exomes 𝑓: 0.050 (218 hom.)
• Consequence: TYMSOS ENST00000323813.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.229
• Publications: 6 publications found

Genes affected

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

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]

ENSG00000263727 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.225 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TYMSOS	NR_171001.1	n.450+384T>C		intron_variant	Intron 1 of 1
TYMS	NM_001071.4	c.-285A>G		upstream_gene_variant		ENST00000323274.15	NP_001062.1
TYMS	NM_001354867.2	c.-285A>G		upstream_gene_variant			NP_001341796.1
TYMS	NM_001354868.2	c.-285A>G		upstream_gene_variant			NP_001341797.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TYMS	ENST00000323274.15	c.-285A>G		upstream_gene_variant		1	NM_001071.4	ENSP00000315644.10

Frequencies

GnomAD3 genomes AF: 0.0967 AC: 14702 AN: 152032 Hom.: 1255 Cov.: 31

Gnomad AFR AF: 0.229

Gnomad AMI AF: 0.00549

Gnomad AMR AF: 0.0529

Gnomad ASJ AF: 0.0597

Gnomad EAS AF: 0.0828

Gnomad SAS AF: 0.0716

Gnomad FIN AF: 0.0392

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0418

Gnomad OTH AF: 0.0837

GnomAD4 exome AF: 0.0496 AC: 5418 AN: 109260 Hom.: 218 AF XY: 0.0479 AC XY: 2690 AN XY: 56122

African (AFR) AF: 0.237 AC: 682 AN: 2874

American (AMR) AF: 0.0418 AC: 127 AN: 3036

Ashkenazi Jewish (ASJ) AF: 0.0605 AC: 240 AN: 3964

East Asian (EAS) AF: 0.0762 AC: 571 AN: 7494

South Asian (SAS) AF: 0.0756 AC: 81 AN: 1072

European-Finnish (FIN) AF: 0.0253 AC: 268 AN: 10574

Middle Eastern (MID) AF: 0.0478 AC: 28 AN: 586

European-Non Finnish (NFE) AF: 0.0411 AC: 2981 AN: 72532

Other (OTH) AF: 0.0617 AC: 440 AN: 7128

GnomAD4 genome AF: 0.0970 AC: 14751 AN: 152150 Hom.: 1261 Cov.: 31 AF XY: 0.0953 AC XY: 7092 AN XY: 74388

African (AFR) AF: 0.229 AC: 9506 AN: 41492

American (AMR) AF: 0.0528 AC: 808 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0597 AC: 207 AN: 3468

East Asian (EAS) AF: 0.0828 AC: 426 AN: 5148

South Asian (SAS) AF: 0.0706 AC: 340 AN: 4816

European-Finnish (FIN) AF: 0.0392 AC: 416 AN: 10614

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.0418 AC: 2844 AN: 68006

Other (OTH) AF: 0.0857 AC: 181 AN: 2112

Alfa AF: 0.0672 Hom.: 120

Bravo AF: 0.103

Asia WGS AF: 0.0820 AC: 287 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	7.0
DANN	Benign	0.56
PhyloP100		0.23
PromoterAI		0.052	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs9952504; hg19: chr18-657458;