chr18-657443-A-C

Variant names:

• chr18-657443-A-C
• rs2606241
• ENST00000323813.6:n.511+399T>G

Variant summary

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

The ENST00000701410.1(TYMSOS):​n.154T>G 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 0.665 in 151,974 control chromosomes in the GnomAD database, including 34,158 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 0.67 (34158 hom., cov: 30)
• Consequence: TYMSOS ENST00000701410.1 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.655
• 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=-0.89).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.716 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000701410.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TYMSOS	NR_171001.1		n.450+399T>G		intron	N/A
	TYMS	NM_001071.4	MANE Select	c.-300A>C		upstream_gene	N/A	NP_001062.1	Q53Y97
	TYMS	NM_001354867.2		c.-300A>C		upstream_gene	N/A	NP_001341796.1	P04818-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TYMSOS	ENST00000323813.6	TSL:1	n.511+399T>G		intron	N/A
	TYMSOS	ENST00000701410.1		n.154T>G		non_coding_transcript_exon	Exon 1 of 2
	TYMSOS	ENST00000585033.1	TSL:2	n.428+399T>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.665 AC: 101030 AN: 151856 Hom.: 34123 Cov.: 30

Gnomad AFR AF: 0.543

Gnomad AMI AF: 0.786

Gnomad AMR AF: 0.726

Gnomad ASJ AF: 0.724

Gnomad EAS AF: 0.519

Gnomad SAS AF: 0.651

Gnomad FIN AF: 0.741

Gnomad MID AF: 0.652

Gnomad NFE AF: 0.721

Gnomad OTH AF: 0.679

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.665 AC: 101115 AN: 151974 Hom.: 34158 Cov.: 30 AF XY: 0.668 AC XY: 49644 AN XY: 74266

African (AFR) AF: 0.543 AC: 22523 AN: 41446

American (AMR) AF: 0.726 AC: 11096 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.724 AC: 2512 AN: 3468

East Asian (EAS) AF: 0.520 AC: 2670 AN: 5134

South Asian (SAS) AF: 0.650 AC: 3125 AN: 4804

European-Finnish (FIN) AF: 0.741 AC: 7837 AN: 10574

Middle Eastern (MID) AF: 0.663 AC: 195 AN: 294

European-Non Finnish (NFE) AF: 0.721 AC: 49019 AN: 67958

Other (OTH) AF: 0.673 AC: 1421 AN: 2110

Alfa AF: 0.604 Hom.: 2482

Bravo AF: 0.657

Asia WGS AF: 0.579 AC: 2012 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.97
DANN	Benign	0.47
PhyloP100		-0.66
PromoterAI		-0.0016	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2606241;

hg19: chr18-657443;