chr22-50527223-A-G

Position:

• chr22-50527223-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_001953.5(TYMP):​c.707T>C​(p.Phe236Ser) 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 Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TYMP NM_001953.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.784

Genes affected

TYMP (HGNC:3148): (thymidine phosphorylase) This gene encodes an angiogenic factor which promotes angiogenesis in vivo and stimulates the in vitro growth of a variety of endothelial cells. It has a highly restricted target cell specificity acting only on endothelial cells. Mutations in this gene have been associated with mitochondrial neurogastrointestinal encephalomyopathy. Multiple alternatively spliced transcript variants have been identified. [provided by RefSeq, Apr 2012]

TYMP (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.885
• PP5: Variant 22-50527223-A-G is Pathogenic according to our data. Variant chr22-50527223-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 223038.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TYMP	NM_001953.5	c.707T>C	p.Phe236Ser	missense_variant	6/10	ENST00000252029.8	NP_001944.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TYMP	ENST00000252029.8	c.707T>C	p.Phe236Ser	missense_variant	6/10	1	NM_001953.5	ENSP00000252029.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Mitochondrial DNA depletion syndrome 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

GeneReviews

Jan 14, 2016

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D;.;D;D;D
Eigen	Benign	-0.085
Eigen_PC	Benign	-0.26
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.93	.;D;.;D;T
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D
MetaSVM	Uncertain	0.79	D
MutationAssessor	Benign	1.5	L;L;L;L;.
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-3.5	D;D;D;D;D
REVEL	Pathogenic	0.70
Sift	Benign	0.034	D;D;D;D;D
Sift4G	Benign	0.35	T;T;T;T;T
Polyphen		0.99	D;.;D;D;.
Vest4		0.49
MutPred		0.83		Loss of catalytic residue at F236 (P = 0.0224);Loss of catalytic residue at F236 (P = 0.0224);Loss of catalytic residue at F236 (P = 0.0224);Loss of catalytic residue at F236 (P = 0.0224);.;
MVP		0.88
MPC		1.6
ClinPred		0.98	D
GERP RS		-0.23
Varity_R		0.83
gMVP		0.93

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: rs1064792868; hg19: chr22-50965652;