rs73366471

Positions:

• chr18-658001-G-A
• chr18-658001-G-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP3 BS1 BS2

The ENST00000323274.15(TYMS):​c.205+54G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00274 in 1,521,696 control chromosomes in the GnomAD database, including 115 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.014 (54 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (61 hom.)
• Consequence: TYMS ENST00000323274.15 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.307

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 -7 ACMG points.

• PP3: BayesDel_noAF computational evidence supports a deleterious effect, 0.15
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0138 (2103/152320) while in subpopulation AFR AF= 0.0465 (1933/41576). AF 95% confidence interval is 0.0448. There are 54 homozygotes in gnomad4. There are 1033 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 54 Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TYMS	NM_001071.4	c.205+54G>A		intron_variant		ENST00000323274.15	NP_001062.1
TYMSOS	NR_171001.1	n.291C>T		non_coding_transcript_exon_variant	1/2
TYMS	NM_001354867.2	c.205+54G>A		intron_variant			NP_001341796.1
TYMS	NM_001354868.2	c.205+54G>A		intron_variant			NP_001341797.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TYMS	ENST00000323274.15	c.205+54G>A		intron_variant		1	NM_001071.4	ENSP00000315644	P1
TYMSOS	ENST00000585033.1	n.269C>T		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes AF: 0.0137 AC: 2084 AN: 152202 Hom.: 52 Cov.: 32

Gnomad AFR AF: 0.0462

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00739

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000367

Gnomad OTH AF: 0.0134

GnomAD3 exomes AF: 0.00378 AC: 516 AN: 136342 Hom.: 16 AF XY: 0.00293 AC XY: 214 AN XY: 72996

Gnomad AFR exome AF: 0.0494

Gnomad AMR exome AF: 0.00397

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000207

Gnomad OTH exome AF: 0.00215

GnomAD4 exome AF: 0.00151 AC: 2074 AN: 1369376 Hom.: 61 Cov.: 31 AF XY: 0.00134 AC XY: 905 AN XY: 672982

Gnomad4 AFR exome AF: 0.0489

Gnomad4 AMR exome AF: 0.00414

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000163

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000160

Gnomad4 OTH exome AF: 0.00399

GnomAD4 genome AF: 0.0138 AC: 2103 AN: 152320 Hom.: 54 Cov.: 32 AF XY: 0.0139 AC XY: 1033 AN XY: 74480

Gnomad4 AFR AF: 0.0465

Gnomad4 AMR AF: 0.00738

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000368

Gnomad4 OTH AF: 0.0133

Alfa AF: 0.000913 Hom.: 0

Bravo AF: 0.0155

Asia WGS AF: 0.00260 AC: 10 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Pathogenic	0.15
CADD	Benign	9.0
DANN	Benign	0.97
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.0

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: rs73366471; hg19: chr18-658001;