18-657685-G-T

Variant names:

• chr18-657685-G-T
• rs2853542
• NM_001071.4:c.-58G>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001071.4(TYMS):​c.-58G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. 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: not found (cov: 16)
  • Exomes 𝑓: 0.0000026 (0 hom.)
• Consequence: TYMS NM_001071.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.372
• Publications: 50 publications found

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

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001071.4. 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
	TYMS	NM_001071.4	MANE Select	c.-58G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 7	NP_001062.1	Q53Y97
	TYMS	NM_001071.4	MANE Select	c.-58G>T		5_prime_UTR	Exon 1 of 7	NP_001062.1	Q53Y97
	TYMS	NM_001354867.2		c.-58G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 6	NP_001341796.1	P04818-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TYMS	ENST00000323274.15	TSL:1 MANE Select	c.-58G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 7	ENSP00000315644.10	P04818-1
	TYMS	ENST00000323274.15	TSL:1 MANE Select	c.-58G>T		5_prime_UTR	Exon 1 of 7	ENSP00000315644.10	P04818-1
	TYMSOS	ENST00000323813.6	TSL:1	n.511+157C>A		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 16

GnomAD4 exome AF: 0.00000261 AC: 1 AN: 383738 Hom.: 0 Cov.: 6 AF XY: 0.00 AC XY: 0 AN XY: 195050

African (AFR) AF: 0.00 AC: 0 AN: 9592

American (AMR) AF: 0.00 AC: 0 AN: 5158

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 7498

East Asian (EAS) AF: 0.00 AC: 0 AN: 19058

South Asian (SAS) AF: 0.00 AC: 0 AN: 17670

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 15912

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1392

European-Non Finnish (NFE) AF: 0.00000346 AC: 1 AN: 289408

Other (OTH) AF: 0.00 AC: 0 AN: 18050

GnomAD4 genome Cov.: 16

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.48
DANN	Benign	0.29
PhyloP100		-0.37
PromoterAI		-0.14	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs2853542; hg19: chr18-657685;