18-658332-C-T

Variant names:

• chr18-658332-C-T
• rs72634355
• ENST00000323813.6:n.21G>A

Variant summary

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

The ENST00000323813.6(TYMSOS):​n.21G>A 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 0.136 in 1,350,480 control chromosomes in the GnomAD database, including 18,372 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 0.18 (3720 hom., cov: 33)
  • Exomes 𝑓: 0.13 (14652 hom.)
• Consequence: TYMSOS ENST00000323813.6 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.07
• 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]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.56 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TYMS	NM_001071.4	c.205+385C>T		intron_variant	Intron 1 of 6	ENST00000323274.15	NP_001062.1
TYMS	NM_001354867.2	c.205+385C>T		intron_variant	Intron 1 of 5		NP_001341796.1
TYMS	NM_001354868.2	c.205+385C>T		intron_variant	Intron 1 of 4		NP_001341797.1
TYMSOS	NR_171001.1	n.-41G>A		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TYMS	ENST00000323274.15	c.205+385C>T		intron_variant	Intron 1 of 6	1	NM_001071.4	ENSP00000315644.10

Frequencies

GnomAD3 genomes AF: 0.185 AC: 28106 AN: 152024 Hom.: 3712 Cov.: 33

Gnomad AFR AF: 0.292

Gnomad AMI AF: 0.0187

Gnomad AMR AF: 0.171

Gnomad ASJ AF: 0.183

Gnomad EAS AF: 0.578

Gnomad SAS AF: 0.328

Gnomad FIN AF: 0.0937

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.0991

Gnomad OTH AF: 0.186

GnomAD4 exome AF: 0.129 AC: 155021 AN: 1198338 Hom.: 14652 Cov.: 32 AF XY: 0.135 AC XY: 79634 AN XY: 588456

African (AFR) AF: 0.298 AC: 7725 AN: 25966

American (AMR) AF: 0.196 AC: 5278 AN: 26904

Ashkenazi Jewish (ASJ) AF: 0.169 AC: 3040 AN: 17984

East Asian (EAS) AF: 0.573 AC: 9819 AN: 17134

South Asian (SAS) AF: 0.317 AC: 24128 AN: 76170

European-Finnish (FIN) AF: 0.0958 AC: 2932 AN: 30598

Middle Eastern (MID) AF: 0.238 AC: 1055 AN: 4442

European-Non Finnish (NFE) AF: 0.0979 AC: 93438 AN: 954174

Other (OTH) AF: 0.169 AC: 7606 AN: 44966

GnomAD4 genome AF: 0.185 AC: 28138 AN: 152142 Hom.: 3720 Cov.: 33 AF XY: 0.189 AC XY: 14079 AN XY: 74378

African (AFR) AF: 0.292 AC: 12116 AN: 41496

American (AMR) AF: 0.172 AC: 2623 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.183 AC: 635 AN: 3472

East Asian (EAS) AF: 0.577 AC: 2965 AN: 5138

South Asian (SAS) AF: 0.327 AC: 1577 AN: 4816

European-Finnish (FIN) AF: 0.0937 AC: 994 AN: 10608

Middle Eastern (MID) AF: 0.221 AC: 65 AN: 294

European-Non Finnish (NFE) AF: 0.0991 AC: 6739 AN: 68006

Other (OTH) AF: 0.193 AC: 407 AN: 2114

Alfa AF: 0.141 Hom.: 4695

Bravo AF: 0.198

Asia WGS AF: 0.425 AC: 1474 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	1.2
DANN	Benign	0.88
PhyloP100		-1.1
Mutation Taster		=100/0	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

Other links and lift over

dbSNP: rs72634355; hg19: chr18-658332; COSMIC: COSV60076222; COSMIC: COSV60076222;