rs761665644

chr22-50527606-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_001953.5(TYMP):c.628A>C(p.Ser210Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,676 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TYMP NM_001953.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.33

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.96
• PP5: Variant 22-50527606-T-G is Pathogenic according to our data. Variant chr22-50527606-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 440502.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TYMP	NM_001953.5	c.628A>C	p.Ser210Arg	missense_variant	5/10	ENST00000252029.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TYMP	ENST00000252029.8	c.628A>C	p.Ser210Arg	missense_variant	5/10	1	NM_001953.5	P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251320 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135876

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: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461676 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 727136

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Mitochondrial DNA depletion syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences

Mar 01, 2016

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.55
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;.;D;D;D
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.0	H;H;H;H;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-4.0	D;D;D;D;D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0070	D;D;D;D;D
Sift4G	Uncertain	0.0070	D;D;D;D;D
Polyphen		1.0	D;.;D;D;.
Vest4		0.87
MutPred		0.86		Loss of glycosylation at T207 (P = 0.0986);Loss of glycosylation at T207 (P = 0.0986);Loss of glycosylation at T207 (P = 0.0986);Loss of glycosylation at T207 (P = 0.0986);.;
MVP		0.98
MPC		1.4
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.99
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: rs761665644; hg19: chr22-50966035;