NM_001953.5:c.1311delG

Variant names:

• chr22-50525907-GC-G
• rs1064792889
• NM_001953.5:c.1311delG

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_001953.5(TYMP):​c.1311delG​(p.Trp437CysfsTer52) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000717 in 1,393,746 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: TYMP NM_001953.5 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.52
• 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: Likely_pathogenic. The variant received 7 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 15 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 22-50525907-GC-G is Pathogenic according to our data. Variant chr22-50525907-GC-G is described in ClinVar as Pathogenic. ClinVar VariationId is 223085.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.1311delG	p.Trp437CysfsTer52	frameshift	Exon 10 of 10	NP_001944.1
	TYMP	NM_001257989.1		c.1326delG	p.Trp442CysfsTer52	frameshift	Exon 10 of 10	NP_001244918.1
	TYMP	NM_001113755.3		c.1311delG	p.Trp437CysfsTer52	frameshift	Exon 10 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.1311delG	p.Trp437CysfsTer52	frameshift	Exon 10 of 10	ENSP00000252029.3
	TYMP	ENST00000395681.6	TSL:1	c.1326delG	p.Trp442CysfsTer52	frameshift	Exon 10 of 10	ENSP00000379038.1
	TYMP	ENST00000395678.7	TSL:1	c.1311delG	p.Trp437CysfsTer51	frameshift	Exon 10 of 10	ENSP00000379036.3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 7.17e-7 AC: 1 AN: 1393746 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 688662

African (AFR) AF: 0.00 AC: 0 AN: 30072

American (AMR) AF: 0.00 AC: 0 AN: 35356

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24066

East Asian (EAS) AF: 0.00 AC: 0 AN: 35600

South Asian (SAS) AF: 0.00 AC: 0 AN: 79142

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47000

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4612

European-Non Finnish (NFE) AF: 9.26e-7 AC: 1 AN: 1080338

Other (OTH) AF: 0.00 AC: 0 AN: 57560

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
PhyloP100		1.5
Mutation Taster		=2/198	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1064792889; hg19: chr22-50964336;