22-50529292-C-G

Variant names:

• chr22-50529292-C-G
• rs749827433
• NM_001953.5:c.261G>C

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PS1 PM2 PP3_Strong PP5

The NM_001953.5(TYMP):​c.261G>C​(p.Glu87Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,080 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 (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Synonymous variant affecting the same amino acid position (i.e. E87E) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TYMP NM_001953.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.38
• Publications: 4 publications found

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 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• mitochondrial DNA depletion syndrome 1

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• mitochondrial neurogastrointestinal encephalomyopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PS1: Transcript NM_001953.5 (TYMP) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983
• PP5: Variant 22-50529292-C-G is Pathogenic according to our data. Variant chr22-50529292-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 223020.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001953.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TYMP	NM_001953.5	MANE Select	c.261G>C	p.Glu87Asp	missense	Exon 3 of 10	NP_001944.1
	TYMP	NM_001257989.1		c.261G>C	p.Glu87Asp	missense	Exon 3 of 10	NP_001244918.1
	TYMP	NM_001113755.3		c.261G>C	p.Glu87Asp	missense	Exon 3 of 10	NP_001107227.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TYMP	ENST00000252029.8	TSL:1 MANE Select	c.261G>C	p.Glu87Asp	missense	Exon 3 of 10	ENSP00000252029.3
	TYMP	ENST00000395681.6	TSL:1	c.261G>C	p.Glu87Asp	missense	Exon 3 of 10	ENSP00000379038.1
	TYMP	ENST00000395678.7	TSL:1	c.261G>C	p.Glu87Asp	missense	Exon 3 of 10	ENSP00000379036.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250360 AF XY: 0.00000737

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461080 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726864

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52656

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111992

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Mitochondrial DNA depletion syndrome 1 Pathogenic:1

Jan 14, 2016

GeneReviews

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.48
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.83	T
M_CAP	Pathogenic	0.62	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.1	H
PhyloP100		2.4
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-2.5	N
REVEL	Pathogenic	0.87
Sift	Benign	0.12	T
Sift4G	Uncertain	0.052	T
Polyphen		0.98	D
Vest4		0.89
MutPred		0.96		Gain of phosphorylation at T88 (P = 0.1705)
MVP		0.93
MPC		0.94
ClinPred		0.99	D
GERP RS		4.2
Varity_R		0.90
gMVP		0.98
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs749827433; hg19: chr22-50967721;