rs3786362

Variant names:

• chr18-662247-A-G
• rs3786362
• NM_001071.4:c.381A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The NM_001071.4(TYMS):​c.381A>G​(p.Glu127Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.011 in 1,613,976 control chromosomes in the GnomAD database, including 973 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.012 (119 hom., cov: 32)
  • Exomes 𝑓: 0.011 (854 hom.)
• Consequence: TYMS NM_001071.4 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.686
• Publications: 31 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]

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 18-662247-A-G is Benign according to our data. Variant chr18-662247-A-G is described in ClinVar as Benign. ClinVar VariationId is 3038406.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=0.686 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.14 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TYMS	NM_001071.4	c.381A>G	p.Glu127Glu	synonymous_variant	Exon 3 of 7	ENST00000323274.15	NP_001062.1
TYMS	NM_001354867.2	c.381A>G	p.Glu127Glu	synonymous_variant	Exon 3 of 6		NP_001341796.1
TYMS	NM_001354868.2	c.205+4300A>G		intron_variant	Intron 1 of 4		NP_001341797.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TYMS	ENST00000323274.15	c.381A>G	p.Glu127Glu	synonymous_variant	Exon 3 of 7	1	NM_001071.4	ENSP00000315644.10
TYMS	ENST00000323224.7	c.381A>G	p.Glu127Glu	synonymous_variant	Exon 3 of 6	1		ENSP00000314727.7
TYMS	ENST00000323250.9	c.205+4300A>G		intron_variant	Intron 1 of 4	1		ENSP00000314902.5
TYMS	ENST00000579128.1	n.459A>G		non_coding_transcript_exon_variant	Exon 3 of 4	2

Frequencies

GnomAD3 genomes AF: 0.0118 AC: 1790 AN: 152178 Hom.: 118 Cov.: 32

Gnomad AFR AF: 0.00200

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0313

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.149

Gnomad SAS AF: 0.0846

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.00908

GnomAD2 exomes AF: 0.0298 AC: 7475 AN: 251258 AF XY: 0.0297

Gnomad AFR exome AF: 0.00191

Gnomad AMR exome AF: 0.0624

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.148

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000448

Gnomad OTH exome AF: 0.0137

GnomAD4 exome AF: 0.0109 AC: 15931 AN: 1461678 Hom.: 854 Cov.: 33 AF XY: 0.0126 AC XY: 9161 AN XY: 727134

African (AFR) AF: 0.00134 AC: 45 AN: 33476

American (AMR) AF: 0.0563 AC: 2513 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.000383 AC: 10 AN: 26134

East Asian (EAS) AF: 0.131 AC: 5214 AN: 39672

South Asian (SAS) AF: 0.0762 AC: 6570 AN: 86170

European-Finnish (FIN) AF: 0.000131 AC: 7 AN: 53418

Middle Eastern (MID) AF: 0.00364 AC: 21 AN: 5766

European-Non Finnish (NFE) AF: 0.000327 AC: 364 AN: 1111982

Other (OTH) AF: 0.0197 AC: 1187 AN: 60386

GnomAD4 genome AF: 0.0117 AC: 1787 AN: 152298 Hom.: 119 Cov.: 32 AF XY: 0.0141 AC XY: 1048 AN XY: 74476

African (AFR) AF: 0.00200 AC: 83 AN: 41574

American (AMR) AF: 0.0314 AC: 481 AN: 15308

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

East Asian (EAS) AF: 0.149 AC: 769 AN: 5168

South Asian (SAS) AF: 0.0845 AC: 406 AN: 4806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000426 AC: 29 AN: 68024

Other (OTH) AF: 0.00899 AC: 19 AN: 2114

Alfa AF: 0.00585 Hom.: 150

Bravo AF: 0.0141

Asia WGS AF: 0.111 AC: 386 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000415

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

TYMS-related disorder Benign:1

Oct 07, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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
BayesDel_noAF	Benign	-0.60
CADD	Benign	5.6
DANN	Benign	0.77
PhyloP100		0.69
Mutation Taster		=96/4	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: rs3786362; hg19: chr18-662247; COSMIC: COSV60074502; COSMIC: COSV60074502;