rs188268314

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr18-657785-C-A
• chr18-657785-C-T
• chr18-657785-C-G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001071.4(TYMS):​c.43C>A​(p.Pro15Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,452,224 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P15H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 7.7e-7 (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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08279255).

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>A	p.Pro15Thr	missense	Exon 1 of 7	NP_001062.1	Q53Y97
	TYMS	NM_001354867.2		c.43C>A	p.Pro15Thr	missense	Exon 1 of 6	NP_001341796.1	P04818-2
	TYMS	NM_001354868.2		c.43C>A	p.Pro15Thr	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>A	p.Pro15Thr	missense	Exon 1 of 7	ENSP00000315644.10	P04818-1
	TYMS	ENST00000323224.7	TSL:1	c.43C>A	p.Pro15Thr	missense	Exon 1 of 6	ENSP00000314727.7	P04818-2
	TYMS	ENST00000323250.9	TSL:1	c.43C>A	p.Pro15Thr	missense	Exon 1 of 5	ENSP00000314902.5	P04818-3

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 7.69e-7 AC: 1 AN: 1300260 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 638578

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 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: 0.00 AC: 0 AN: 28412

South Asian (SAS) AF: 0.00 AC: 0 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: 9.60e-7 AC: 1 AN: 1041354

Other (OTH) AF: 0.00 AC: 0 AN: 53826

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151964 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74230

African (AFR) AF: 0.0000242 AC: 1 AN: 41368

American (AMR) AF: 0.00 AC: 0 AN: 15272

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67966

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	6.8
DANN	Benign	0.87
DEOGEN2	Benign	0.18	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.083	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
PhyloP100		0.074
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.20	N
REVEL	Benign	0.021
Sift	Benign	0.087	T
Sift4G	Benign	0.14	T
Polyphen		0.20	B
Vest4		0.11
MutPred		0.29		Gain of phosphorylation at P15 (P = 0.0149)
MVP		0.068
MPC		0.97
ClinPred		0.11	T
GERP RS		-2.6
PromoterAI		0.020	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		3.9
Varity_R		0.074
gMVP		0.21
Mutation Taster		=94/6	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;