rs1064792994

Variant names:

• chr22-50526143-T-C
• rs1064792877
• ENST00000395681.6:c.1173A>G

Your query was ambiguous. Multiple possible variants found:

• chr22-50526143-T-C
• chr22-50526143-T-G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The ENST00000395681.6(TYMP):​c.1173A>G​(p.Ala391Ala) variant causes a synonymous 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). Synonymous variant affecting the same amino acid position (i.e. A391A) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TYMP ENST00000395681.6 synonymous
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.01
• Publications: 2 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.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 22-50526143-T-C is Pathogenic according to our data. Variant chr22-50526143-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 223068.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TYMP	NM_001953.5	c.1160-2A>G		splice_acceptor_variant, intron_variant	Intron 8 of 9	ENST00000252029.8	NP_001944.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TYMP	ENST00000252029.8	c.1160-2A>G		splice_acceptor_variant, intron_variant	Intron 8 of 9	1	NM_001953.5	ENSP00000252029.3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1331056 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 655870

African (AFR) AF: 0.00 AC: 0 AN: 26806

American (AMR) AF: 0.00 AC: 0 AN: 29372

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22766

East Asian (EAS) AF: 0.00 AC: 0 AN: 30662

South Asian (SAS) AF: 0.00 AC: 0 AN: 73212

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32828

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4654

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1055284

Other (OTH) AF: 0.00 AC: 0 AN: 55472

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

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Benign	-0.42
CADD	Benign	23
DANN	Benign	0.96
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.84	D
PhyloP100		2.0
GERP RS		3.2
PromoterAI		-0.034	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=12/88	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.92		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.92		Position offset: -2

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

Other links and lift over

dbSNP: rs1064792877; hg19: chr22-50964572;