18-657785-C-T

Position:

• chr18-657785-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001071.4(TYMS):​c.43C>T​(p.Pro15Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00539 in 1,452,330 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0056 (41 hom.)
• Consequence: TYMS NM_001071.4 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.0740

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

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0034260154).
• BP6: Variant 18-657785-C-T is Benign according to our data. Variant chr18-657785-C-T is described in ClinVar as [Benign]. Clinvar id is 3055385.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High Homozygotes in GnomAdExome4 at 41 Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TYMS	NM_001071.4	c.43C>T	p.Pro15Ser	missense_variant	1/7	ENST00000323274.15
TYMSOS	NR_171001.1	n.450+57G>A		intron_variant, non_coding_transcript_variant
TYMS	NM_001354867.2	c.43C>T	p.Pro15Ser	missense_variant	1/6
TYMS	NM_001354868.2	c.43C>T	p.Pro15Ser	missense_variant	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TYMS	ENST00000323274.15	c.43C>T	p.Pro15Ser	missense_variant	1/7	1	NM_001071.4	P1
TYMSOS	ENST00000585033.1	n.428+57G>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00386 AC: 587 AN: 151964 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00133

Gnomad AMI AF: 0.00440

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.0193

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000851

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00590

Gnomad OTH AF: 0.00288

GnomAD3 exomes AF: 0.00424 AC: 217 AN: 51128 Hom.: 0 AF XY: 0.00453 AC XY: 135 AN XY: 29806

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00182

Gnomad ASJ exome AF: 0.0214

Gnomad EAS exome AF: 0.000720

Gnomad SAS exome AF: 0.000302

Gnomad FIN exome AF: 0.00140

Gnomad NFE exome AF: 0.00596

Gnomad OTH exome AF: 0.00329

GnomAD4 exome AF: 0.00557 AC: 7243 AN: 1300256 Hom.: 41 Cov.: 31 AF XY: 0.00549 AC XY: 3506 AN XY: 638576

Gnomad4 AFR exome AF: 0.000788

Gnomad4 AMR exome AF: 0.00254

Gnomad4 ASJ exome AF: 0.0218

Gnomad4 EAS exome AF: 0.0000704

Gnomad4 SAS exome AF: 0.000440

Gnomad4 FIN exome AF: 0.000837

Gnomad4 NFE exome AF: 0.00607

Gnomad4 OTH exome AF: 0.00596

GnomAD4 genome AF: 0.00386 AC: 587 AN: 152074 Hom.: 0 Cov.: 32 AF XY: 0.00374 AC XY: 278 AN XY: 74350

Gnomad4 AFR AF: 0.00133

Gnomad4 AMR AF: 0.00288

Gnomad4 ASJ AF: 0.0193

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000851

Gnomad4 NFE AF: 0.00590

Gnomad4 OTH AF: 0.00285

Alfa AF: 0.00308 Hom.: 0

Bravo AF: 0.00406

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00187 AC: 12

ExAC AF: 0.00211 AC: 195

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

TYMS-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 21, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	6.8
DANN	Benign	0.83
DEOGEN2	Benign	0.17	T;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.66	T;T;T
MetaRNN	Benign	0.0034	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L;L;L
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	0.010	N;N;N
REVEL	Benign	0.022
Sift	Benign	0.24	T;D;T
Sift4G	Benign	0.20	T;T;T
Polyphen		0.049	B;.;.
Vest4		0.22
MVP		0.068
MPC		0.88
ClinPred		0.014	T
GERP RS		-2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		3.9
Varity_R		0.057
gMVP		0.19

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

Publications

LitVar

Other links and lift over

dbSNP: rs188268314; hg19: chr18-657785;