rs797044455

Variant names:

• chr22-50526142-C-G
• rs797044455
• ENST00000395681.6:c.1174G>C

Your query was ambiguous. Multiple possible variants found:

• chr22-50526142-C-G
• chr22-50526142-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PM5 PP3_Moderate PP5

The ENST00000395681.6(TYMP):​c.1174G>C​(p.Gly392Arg) variant causes a missense 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G392S) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 34)
• Consequence: TYMP ENST00000395681.6 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 1.29
• Publications: 5 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.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr22-50526142-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 223064.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 22-50526142-C-G is Pathogenic according to our data. Variant chr22-50526142-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 16658.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000395681.6. 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.1160-1G>C		splice_acceptor intron	N/A	NP_001944.1
	TYMP	NM_001257989.1		c.1174G>C	p.Gly392Arg	missense	Exon 9 of 10	NP_001244918.1
	SCO2	NM_001169110.1		c.-155G>C		5_prime_UTR	Exon 1 of 2	NP_001162581.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TYMP	ENST00000395681.6	TSL:1	c.1174G>C	p.Gly392Arg	missense	Exon 9 of 10	ENSP00000379038.1
	TYMP	ENST00000252029.8	TSL:1 MANE Select	c.1160-1G>C		splice_acceptor intron	N/A	ENSP00000252029.3
	TYMP	ENST00000395678.7	TSL:1	c.1160-1G>C		splice_acceptor intron	N/A	ENSP00000379036.3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
2	-	-	Mitochondrial DNA depletion syndrome 1 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.32
CADD	Benign	23
DANN	Uncertain	0.98
Eigen	Benign	0.18
Eigen_PC	Benign	0.069
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Pathogenic	0.78	D
PhyloP100		1.3
ClinPred		1.0	D
GERP RS		3.2
PromoterAI		-0.12	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=11/89	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.91		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.91		Position offset: -1

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

Other links and lift over

dbSNP: rs797044455; hg19: chr22-50964571;