18-661005-A-G

Variant names:

• chr18-661005-A-G
• rs2244500
• NM_001071.4:c.280-1141A>G

Variant summary

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

The NM_001071.4(TYMS):​c.280-1141A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.553 in 151,990 control chromosomes in the GnomAD database, including 24,838 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 0.55 (24838 hom., cov: 32)
• Consequence: TYMS NM_001071.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.903
• Publications: 25 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.772 is higher than 0.05.

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.280-1141A>G		intron	N/A	NP_001062.1	Q53Y97
	TYMS	NM_001354867.2		c.280-1141A>G		intron	N/A	NP_001341796.1	P04818-2
	TYMS	NM_001354868.2		c.205+3058A>G		intron	N/A	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.280-1141A>G		intron	N/A	ENSP00000315644.10	P04818-1
	TYMS	ENST00000323224.7	TSL:1	c.280-1141A>G		intron	N/A	ENSP00000314727.7	P04818-2
	TYMS	ENST00000323250.9	TSL:1	c.205+3058A>G		intron	N/A	ENSP00000314902.5	P04818-3

Frequencies

GnomAD3 genomes AF: 0.553 AC: 83933 AN: 151872 Hom.: 24793 Cov.: 32

Gnomad AFR AF: 0.779

Gnomad AMI AF: 0.334

Gnomad AMR AF: 0.429

Gnomad ASJ AF: 0.485

Gnomad EAS AF: 0.684

Gnomad SAS AF: 0.549

Gnomad FIN AF: 0.450

Gnomad MID AF: 0.608

Gnomad NFE AF: 0.456

Gnomad OTH AF: 0.545

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.553 AC: 84019 AN: 151990 Hom.: 24838 Cov.: 32 AF XY: 0.552 AC XY: 41008 AN XY: 74270

African (AFR) AF: 0.779 AC: 32288 AN: 41460

American (AMR) AF: 0.428 AC: 6528 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.485 AC: 1684 AN: 3470

East Asian (EAS) AF: 0.683 AC: 3531 AN: 5168

South Asian (SAS) AF: 0.547 AC: 2633 AN: 4814

European-Finnish (FIN) AF: 0.450 AC: 4754 AN: 10558

Middle Eastern (MID) AF: 0.605 AC: 178 AN: 294

European-Non Finnish (NFE) AF: 0.456 AC: 30962 AN: 67964

Other (OTH) AF: 0.551 AC: 1160 AN: 2106

Alfa AF: 0.486 Hom.: 31270

Bravo AF: 0.561

Asia WGS AF: 0.634 AC: 2208 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.81
DANN	Benign	0.64
PhyloP100		-0.90
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: rs2244500; hg19: chr18-661005;