chr18-657474-T-C

Variant names:

• chr18-657474-T-C
• rs2853742
• ENST00000323813.6:n.511+368A>G

Variant summary

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

The ENST00000323813.6(TYMSOS):​n.511+368A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.275 in 272,772 control chromosomes in the GnomAD database, including 10,597 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 0.26 (5395 hom., cov: 31)
  • Exomes 𝑓: 0.29 (5202 hom.)
• Consequence: TYMSOS ENST00000323813.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.53
• Publications: 7 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=-0.82).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.273 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000323813.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TYMSOS	NR_171001.1		n.450+368A>G		intron	N/A
	TYMS	NM_001071.4	MANE Select	c.-269T>C		upstream_gene	N/A	NP_001062.1
	TYMS	NM_001354867.2		c.-269T>C		upstream_gene	N/A	NP_001341796.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TYMSOS	ENST00000323813.6	TSL:1	n.511+368A>G		intron	N/A
	TYMSOS	ENST00000688642.3		n.125A>G		non_coding_transcript_exon	Exon 1 of 2
	TYMSOS	ENST00000701410.1		n.123A>G		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes AF: 0.264 AC: 40114 AN: 151900 Hom.: 5393 Cov.: 31

Gnomad AFR AF: 0.236

Gnomad AMI AF: 0.216

Gnomad AMR AF: 0.263

Gnomad ASJ AF: 0.279

Gnomad EAS AF: 0.143

Gnomad SAS AF: 0.253

Gnomad FIN AF: 0.362

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.276

Gnomad OTH AF: 0.257

GnomAD4 exome AF: 0.289 AC: 34839 AN: 120754 Hom.: 5202 AF XY: 0.289 AC XY: 17937 AN XY: 62038

African (AFR) AF: 0.241 AC: 757 AN: 3142

American (AMR) AF: 0.300 AC: 1009 AN: 3364

Ashkenazi Jewish (ASJ) AF: 0.297 AC: 1286 AN: 4336

East Asian (EAS) AF: 0.179 AC: 1559 AN: 8710

South Asian (SAS) AF: 0.279 AC: 321 AN: 1150

European-Finnish (FIN) AF: 0.375 AC: 4401 AN: 11730

Middle Eastern (MID) AF: 0.189 AC: 122 AN: 644

European-Non Finnish (NFE) AF: 0.291 AC: 23251 AN: 79906

Other (OTH) AF: 0.274 AC: 2133 AN: 7772

GnomAD4 genome AF: 0.264 AC: 40141 AN: 152018 Hom.: 5395 Cov.: 31 AF XY: 0.267 AC XY: 19833 AN XY: 74298

African (AFR) AF: 0.236 AC: 9792 AN: 41484

American (AMR) AF: 0.264 AC: 4032 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.279 AC: 967 AN: 3466

East Asian (EAS) AF: 0.143 AC: 736 AN: 5140

South Asian (SAS) AF: 0.253 AC: 1218 AN: 4810

European-Finnish (FIN) AF: 0.362 AC: 3832 AN: 10578

Middle Eastern (MID) AF: 0.201 AC: 59 AN: 294

European-Non Finnish (NFE) AF: 0.276 AC: 18767 AN: 67940

Other (OTH) AF: 0.256 AC: 541 AN: 2114

Alfa AF: 0.273 Hom.: 1270

Bravo AF: 0.258

Asia WGS AF: 0.184 AC: 642 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	8.3
DANN	Benign	0.65
PhyloP100		1.5
PromoterAI		-0.0059	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
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: rs2853742; hg19: chr18-657474;