NM_001071.4:c.280-43G>A

Variant names:

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

Variant summary

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

The NM_001071.4(TYMS):​c.280-43G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.483 in 1,553,636 control chromosomes in the GnomAD database, including 186,891 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 (24727 hom., cov: 31)
  • Exomes 𝑓: 0.48 (162164 hom.)
• 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.769 is higher than 0.05.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.552 AC: 83794 AN: 151882 Hom.: 24681 Cov.: 31

Gnomad AFR AF: 0.776

Gnomad AMI AF: 0.330

Gnomad AMR AF: 0.428

Gnomad ASJ AF: 0.485

Gnomad EAS AF: 0.683

Gnomad SAS AF: 0.549

Gnomad FIN AF: 0.450

Gnomad MID AF: 0.608

Gnomad NFE AF: 0.456

Gnomad OTH AF: 0.543

GnomAD2 exomes AF: 0.503 AC: 101620 AN: 202044 AF XY: 0.502

Gnomad AFR exome AF: 0.783

Gnomad AMR exome AF: 0.378

Gnomad ASJ exome AF: 0.470

Gnomad EAS exome AF: 0.689

Gnomad FIN exome AF: 0.459

Gnomad NFE exome AF: 0.463

Gnomad OTH exome AF: 0.480

GnomAD4 exome AF: 0.476 AC: 666635 AN: 1401636 Hom.: 162164 Cov.: 30 AF XY: 0.477 AC XY: 330661 AN XY: 693288

African (AFR) AF: 0.788 AC: 24630 AN: 31262

American (AMR) AF: 0.384 AC: 13687 AN: 35676

Ashkenazi Jewish (ASJ) AF: 0.473 AC: 10403 AN: 21986

East Asian (EAS) AF: 0.665 AC: 25794 AN: 38812

South Asian (SAS) AF: 0.542 AC: 40613 AN: 75000

European-Finnish (FIN) AF: 0.455 AC: 22973 AN: 50504

Middle Eastern (MID) AF: 0.584 AC: 2634 AN: 4514

European-Non Finnish (NFE) AF: 0.457 AC: 496884 AN: 1086166

Other (OTH) AF: 0.503 AC: 29017 AN: 57716

GnomAD4 genome AF: 0.552 AC: 83882 AN: 152000 Hom.: 24727 Cov.: 31 AF XY: 0.551 AC XY: 40969 AN XY: 74330

African (AFR) AF: 0.776 AC: 32180 AN: 41470

American (AMR) AF: 0.427 AC: 6539 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.485 AC: 1684 AN: 3472

East Asian (EAS) AF: 0.682 AC: 3501 AN: 5130

South Asian (SAS) AF: 0.547 AC: 2635 AN: 4816

European-Finnish (FIN) AF: 0.450 AC: 4749 AN: 10564

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

European-Non Finnish (NFE) AF: 0.456 AC: 30958 AN: 67934

Other (OTH) AF: 0.548 AC: 1158 AN: 2112

Alfa AF: 0.510 Hom.: 33203

Bravo AF: 0.560

Asia WGS AF: 0.633 AC: 2205 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.1
DANN	Benign	0.37
PhyloP100		0.12
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs1001761; hg19: chr18-662103; COSMIC: COSV60074405; COSMIC: COSV60074405;