18-669097-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001071.4(TYMS):c.480A>T(p.Gln160His) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TYMS NM_001071.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 1.33

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:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TYMS	NM_001071.4	c.480A>T	p.Gln160His	missense_variant	4/7	ENST00000323274.15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TYMS	ENST00000323274.15	c.480A>T	p.Gln160His	missense_variant	4/7	1	NM_001071.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Dyskeratosis congenita, digenic Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 22, 2022

- -

Dyskeratosis congenita Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Bone Marrow Failure laboratory, Queen Mary University London

Jun 22, 2022

This heterozygous missense variant of TYMS was identified in a 26-year old female with dyskeratosis congenita. The following ACMG/AMP criteria were used: PM2_supporting -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
Cadd	Benign	22
Dann	Benign	0.97
DEOGEN2	Pathogenic	0.80	D;.
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.63
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Benign	0.075	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Uncertain	0.51	D
MutationAssessor	Pathogenic	4.8	H;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-4.6	D;D
REVEL	Uncertain	0.62
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.91
MutPred		0.91		Loss of disorder (P = 0.1946);.;
MVP		0.75
MPC		1.9
ClinPred		1.0	D
GERP RS		-10
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.99

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr18-669097;