18-657785-C-G

Variant names:

• chr18-657785-C-G
• rs188268314
• NM_001071.4:c.43C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001071.4(TYMS):​c.43C>G​(p.Pro15Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000365 in 1,452,334 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P15T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000039 (1 hom., cov: 32)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: TYMS NM_001071.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0740
• Publications: 4 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 -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07779148).

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.43C>G	p.Pro15Ala	missense	Exon 1 of 7	NP_001062.1	Q53Y97
	TYMS	NM_001354867.2		c.43C>G	p.Pro15Ala	missense	Exon 1 of 6	NP_001341796.1	P04818-2
	TYMS	NM_001354868.2		c.43C>G	p.Pro15Ala	missense	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.43C>G	p.Pro15Ala	missense	Exon 1 of 7	ENSP00000315644.10	P04818-1
	TYMS	ENST00000323224.7	TSL:1	c.43C>G	p.Pro15Ala	missense	Exon 1 of 6	ENSP00000314727.7	P04818-2
	TYMS	ENST00000323250.9	TSL:1	c.43C>G	p.Pro15Ala	missense	Exon 1 of 5	ENSP00000314902.5	P04818-3

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151964 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000361 AC: 47 AN: 1300260 Hom.: 0 Cov.: 31 AF XY: 0.0000345 AC XY: 22 AN XY: 638578

African (AFR) AF: 0.000591 AC: 15 AN: 25380

American (AMR) AF: 0.00 AC: 0 AN: 20084

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20826

East Asian (EAS) AF: 0.0000352 AC: 1 AN: 28412

South Asian (SAS) AF: 0.0000152 AC: 1 AN: 65858

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39446

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5074

European-Non Finnish (NFE) AF: 0.0000115 AC: 12 AN: 1041354

Other (OTH) AF: 0.000334 AC: 18 AN: 53826

GnomAD4 genome AF: 0.0000395 AC: 6 AN: 152074 Hom.: 1 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74350

African (AFR) AF: 0.000121 AC: 5 AN: 41486

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10572

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67956

Other (OTH) AF: 0.00 AC: 0 AN: 2106

Alfa AF: 0.00 Hom.: 0

Asia WGS AF: 0.00145 AC: 5 AN: 3464

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.050
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	2.4
DANN	Benign	0.67
DEOGEN2	Benign	0.18	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.078	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.074
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.22	N
REVEL	Benign	0.037
Sift	Benign	0.19	T
Sift4G	Benign	0.24	T
Polyphen		0.0010	B
Vest4		0.17
MutPred		0.25		Loss of glycosylation at P15 (P = 0.0218)
MVP		0.068
MPC		0.86
ClinPred		0.11	T
GERP RS		-2.6
PromoterAI		0.15	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		3.9
Varity_R		0.051
gMVP		0.16
Mutation Taster		=95/5	polymorphism

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: rs188268314; hg19: chr18-657785;