18-657685-G-C

Variant names:

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

Variant summary

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

The NM_001071.4(TYMS):​c.-58G>C variant causes a 5 prime UTR 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: 𝑓 0.44 (5506 hom., cov: 16)
  • Exomes 𝑓: 0.36 (14851 hom.)
  • Failed GnomAD Quality Control
• Consequence: TYMS NM_001071.4 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.372
• Publications: 51 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.498 is higher than 0.05.

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>C		5_prime_UTR	Exon 1 of 7	NP_001062.1	Q53Y97
	TYMS	NM_001354867.2		c.-58G>C		5_prime_UTR	Exon 1 of 6	NP_001341796.1	P04818-2
	TYMS	NM_001354868.2		c.-58G>C		5_prime_UTR	Exon 1 of 5	NP_001341797.1	P04818-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TYMS	ENST00000323274.15	TSL:1 MANE Select	c.-58G>C		5_prime_UTR	Exon 1 of 7	ENSP00000315644.10	P04818-1
	TYMSOS	ENST00000323813.6	TSL:1	n.511+157C>G		intron	N/A
	TYMS	ENST00000918013.1		c.-58G>C		5_prime_UTR	Exon 1 of 7	ENSP00000588072.1

Frequencies

GnomAD3 genomes AF: 0.439 AC: 38406 AN: 87512 Hom.: 5510 Cov.: 16

Gnomad AFR AF: 0.261

Gnomad AMI AF: 0.574

Gnomad AMR AF: 0.504

Gnomad ASJ AF: 0.476

Gnomad EAS AF: 0.426

Gnomad SAS AF: 0.415

Gnomad FIN AF: 0.550

Gnomad MID AF: 0.429

Gnomad NFE AF: 0.504

Gnomad OTH AF: 0.443

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.364 AC: 130919 AN: 359768 Hom.: 14851 Cov.: 6 AF XY: 0.368 AC XY: 67406 AN XY: 183284

African (AFR) AF: 0.152 AC: 1415 AN: 9292

American (AMR) AF: 0.438 AC: 2201 AN: 5030

Ashkenazi Jewish (ASJ) AF: 0.393 AC: 2856 AN: 7268

East Asian (EAS) AF: 0.401 AC: 7483 AN: 18682

South Asian (SAS) AF: 0.285 AC: 4889 AN: 17182

European-Finnish (FIN) AF: 0.507 AC: 7941 AN: 15662

Middle Eastern (MID) AF: 0.312 AC: 412 AN: 1320

European-Non Finnish (NFE) AF: 0.363 AC: 97460 AN: 268146

Other (OTH) AF: 0.364 AC: 6262 AN: 17186

GnomAD4 genome AF: 0.439 AC: 38422 AN: 87588 Hom.: 5506 Cov.: 16 AF XY: 0.440 AC XY: 18853 AN XY: 42806

African (AFR) AF: 0.261 AC: 5675 AN: 21746

American (AMR) AF: 0.503 AC: 4847 AN: 9634

Ashkenazi Jewish (ASJ) AF: 0.476 AC: 944 AN: 1984

East Asian (EAS) AF: 0.425 AC: 1697 AN: 3992

South Asian (SAS) AF: 0.415 AC: 1201 AN: 2896

European-Finnish (FIN) AF: 0.550 AC: 3191 AN: 5800

Middle Eastern (MID) AF: 0.423 AC: 60 AN: 142

European-Non Finnish (NFE) AF: 0.504 AC: 19980 AN: 39668

Other (OTH) AF: 0.439 AC: 532 AN: 1212

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	-0.86
CADD	Benign	0.47
DANN	Benign	0.32
PhyloP100		-0.37
PromoterAI		-0.083	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Mutation Taster		=300/0	polymorphism (auto)

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

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

Other links and lift over

dbSNP: rs2853542;

hg19: chr18-657685;

COSMIC: COSV60075644;

COSMIC: COSV60075644;