rs2790

chr18-673086-A-Gchr18-673086-A-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000383578.7(ENOSF1):c.*145-10T>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.218 in 1,377,150 control chromosomes in the GnomAD database, including 34,173 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.23 (4066 hom., cov: 32)
  • Exomes 𝑓: 0.22 (30107 hom.)
• Consequence: ENOSF1 ENST00000383578.7 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00003376
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.707

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]

ENOSF1 (HGNC:30365): (enolase superfamily member 1) This gene can encode a mitochondrial enzyme that is thought to convert L-fuconate to 2-keto-3-deoxy-L-fuconate. This locus was originally identified as the source of antisense RNAs of the adjacent thymidylate synthase gene. Splice variants at this locus may contain an alternate 3' exon that is complementary to the 3'UTR and terminal intron of the thymidylate synthase (TS) RNA and may downregulate TS expression. [provided by RefSeq, Aug 2017]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 18-673086-A-G is Benign according to our data. Variant chr18-673086-A-G is described in ClinVar as [Benign]. Clinvar id is 1234187.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.355 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TYMS	NM_001071.4	c.*89A>G		3_prime_UTR_variant	7/7	ENST00000323274.15
ENOSF1	NM_017512.7	c.*1219T>C		3_prime_UTR_variant	16/16	ENST00000647584.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TYMS	ENST00000323274.15	c.*89A>G		3_prime_UTR_variant	7/7	1	NM_001071.4	P1
ENOSF1	ENST00000647584.2	c.*1219T>C		3_prime_UTR_variant	16/16		NM_017512.7	P1

Frequencies

GnomAD3 genomes AF: 0.226 AC: 34419 AN: 152052 Hom.: 4065 Cov.: 32

Gnomad AFR AF: 0.250

Gnomad AMI AF: 0.0537

Gnomad AMR AF: 0.217

Gnomad ASJ AF: 0.255

Gnomad EAS AF: 0.370

Gnomad SAS AF: 0.356

Gnomad FIN AF: 0.164

Gnomad MID AF: 0.291

Gnomad NFE AF: 0.204

Gnomad OTH AF: 0.236

GnomAD4 exome AF: 0.217 AC: 265510 AN: 1224980 Hom.: 30107 Cov.: 19 AF XY: 0.220 AC XY: 131461 AN XY: 596762

Gnomad4 AFR exome AF: 0.260

Gnomad4 AMR exome AF: 0.225

Gnomad4 ASJ exome AF: 0.244

Gnomad4 EAS exome AF: 0.389

Gnomad4 SAS exome AF: 0.356

Gnomad4 FIN exome AF: 0.165

Gnomad4 NFE exome AF: 0.202

Gnomad4 OTH exome AF: 0.237

GnomAD4 genome AF: 0.226 AC: 34437 AN: 152170 Hom.: 4066 Cov.: 32 AF XY: 0.229 AC XY: 17064 AN XY: 74394

Gnomad4 AFR AF: 0.250

Gnomad4 AMR AF: 0.217

Gnomad4 ASJ AF: 0.255

Gnomad4 EAS AF: 0.369

Gnomad4 SAS AF: 0.355

Gnomad4 FIN AF: 0.164

Gnomad4 NFE AF: 0.204

Gnomad4 OTH AF: 0.241

Alfa AF: 0.216 Hom.: 3717

Bravo AF: 0.231

Asia WGS AF: 0.383 AC: 1336 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 15, 2020

This variant is associated with the following publications: (PMID: 24997136) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	9.3
Dann	Benign	0.47
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000034
dbscSNV1_RF	Benign	0.010
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: rs2790; hg19: chr18-673086;