18-671433-C-G

Variant names:

• chr18-671433-C-G
• rs143415597
• NM_001071.4:c.786C>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001071.4(TYMS):​c.786C>G​(p.Ile262Met) variant causes a missense 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. 15/20 in silico tools predict 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: 33)
• Consequence: TYMS NM_001071.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.89

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.043886214).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TYMS	NM_001071.4	c.786C>G	p.Ile262Met	missense_variant	Exon 6 of 7	ENST00000323274.15	NP_001062.1
ENOSF1	NM_017512.7	c.*2872G>C		3_prime_UTR_variant	Exon 16 of 16	ENST00000647584.2	NP_059982.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TYMS	ENST00000323274.15	c.786C>G	p.Ile262Met	missense_variant	Exon 6 of 7	1	NM_001071.4	ENSP00000315644.10
ENOSF1	ENST00000647584	c.*2872G>C		3_prime_UTR_variant	Exon 16 of 16		NM_017512.7	ENSP00000497230.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000363 AC: 9 AN: 248136 Hom.: 0 AF XY: 0.0000299 AC XY: 4 AN XY: 133956

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000371

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ExAC AF: 0.000173 AC: 21

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	0.40
DANN	Benign	0.96
DEOGEN2	Uncertain	0.51	D;.;.
Eigen	Benign	-0.98
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.42	N
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.044	T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.8	L;.;.
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-2.3	N;N;N
REVEL	Benign	0.16
Sift	Uncertain	0.0090	D;D;D
Sift4G	Benign	0.10	T;T;T
Polyphen		0.56	P;.;.
Vest4		0.29
MutPred		0.48		Loss of catalytic residue at P264 (P = 0.0284);.;.;
MVP		0.12
MPC		2.0
ClinPred		0.37	T
GERP RS		-2.4
Varity_R		0.47
gMVP		0.80

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: rs143415597; hg19: chr18-671433;