22-50525999-A-T

Variant names:

• chr22-50525999-A-T
• rs1064792879
• NM_001953.5:c.1300+2T>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PVS1_Moderate PM2 PP5

The NM_001953.5(TYMP):​c.1300+2T>A variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TYMP NM_001953.5 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.274
• Publications: 0 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]

SCO2 (HGNC:10604): (synthesis of cytochrome C oxidase 2) Cytochrome c oxidase (COX) catalyzes the transfer of electrons from cytochrome c to molecular oxygen, which helps to maintain the proton gradient across the inner mitochondrial membrane that is necessary for aerobic ATP production. Human COX is a multimeric protein complex that requires several assembly factors; this gene encodes one of the COX assembly factors. The encoded protein is a metallochaperone that is involved in the biogenesis of cytochrome c oxidase subunit II. Mutations in this gene are associated with fatal infantile encephalocardiomyopathy and myopia 6. [provided by RefSeq, Oct 2014]

SCO2 Gene-Disease associations (from GenCC):

• cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• Leigh syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• myopia 6

  Inheritance: AD Classification: STRONG Submitted by: G2P
• autosomal recessive axonal charcot-marie-tooth disease due to copper metabolism defect

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.09730849 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.5, offset of -22, new splice context is: gacGTgggt. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 22-50525999-A-T is Pathogenic according to our data. Variant chr22-50525999-A-T is described in ClinVar as Pathogenic. ClinVar VariationId is 223070.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.1300+2T>A		splice_donor intron	N/A	NP_001944.1
	TYMP	NM_001257989.1		c.1315+2T>A		splice_donor intron	N/A	NP_001244918.1
	TYMP	NM_001113755.3		c.1300+2T>A		splice_donor intron	N/A	NP_001107227.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TYMP	ENST00000252029.8	TSL:1 MANE Select	c.1300+2T>A		splice_donor intron	N/A	ENSP00000252029.3
	TYMP	ENST00000395681.6	TSL:1	c.1315+2T>A		splice_donor intron	N/A	ENSP00000379038.1
	TYMP	ENST00000395678.7	TSL:1	c.1300+2T>A		splice_donor intron	N/A	ENSP00000379036.3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1271006 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 624886

African (AFR) AF: 0.00 AC: 0 AN: 25072

American (AMR) AF: 0.00 AC: 0 AN: 18936

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20842

East Asian (EAS) AF: 0.00 AC: 0 AN: 27940

South Asian (SAS) AF: 0.00 AC: 0 AN: 64228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32000

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3746

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1025906

Other (OTH) AF: 0.00 AC: 0 AN: 52336

GnomAD4 genome Cov.: 34

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
BayesDel_addAF	Uncertain	0.029	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	23
DANN	Benign	0.93
Eigen	Uncertain	0.30
Eigen_PC	Benign	-0.040
FATHMM_MKL	Uncertain	0.80	D
PhyloP100		0.27
GERP RS		2.8
PromoterAI		-0.00070	Neutral
Mutation Taster		=12/88	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.95
SpliceAI score (max)		0.93		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.93		Position offset: 2

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

Other links and lift over

dbSNP: rs1064792879; hg19: chr22-50964428;