18-662103-G-T

Variant names:

• chr18-662103-G-T
• rs1001761
• NM_001071.4:c.280-43G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001071.4(TYMS):​c.280-43G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TYMS NM_001071.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.115
• Publications: 40 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TYMS	NM_001071.4	c.280-43G>T		intron_variant	Intron 2 of 6	ENST00000323274.15	NP_001062.1
TYMS	NM_001354867.2	c.280-43G>T		intron_variant	Intron 2 of 5		NP_001341796.1
TYMS	NM_001354868.2	c.205+4156G>T		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.280-43G>T		intron_variant	Intron 2 of 6	1	NM_001071.4	ENSP00000315644.10
TYMS	ENST00000323224.7	c.280-43G>T		intron_variant	Intron 2 of 5	1		ENSP00000314727.7
TYMS	ENST00000323250.9	c.205+4156G>T		intron_variant	Intron 1 of 4	1		ENSP00000314902.5
TYMS	ENST00000579128.1	n.358-43G>T		intron_variant	Intron 2 of 3	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1402870 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 693918

African (AFR) AF: 0.00 AC: 0 AN: 31280

American (AMR) AF: 0.00 AC: 0 AN: 35766

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22020

East Asian (EAS) AF: 0.00 AC: 0 AN: 38848

South Asian (SAS) AF: 0.00 AC: 0 AN: 75138

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50562

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4520

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1086980

Other (OTH) AF: 0.00 AC: 0 AN: 57756

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.5
DANN	Benign	0.48
PhyloP100		0.12
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs1001761; hg19: chr18-662103;