rs1064792871

Variant names:

• chr22-50526657-G-C
• rs1064792871
• NM_001953.5:c.847C>G

Your query was ambiguous. Multiple possible variants found:

• chr22-50526657-G-C
• chr22-50526657-G-A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_001953.5(TYMP):​c.847C>G​(p.His283Asp) 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 Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. H283H) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TYMP NM_001953.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 1.35
• 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), PanelApp Australia, G2P
• Leigh syndrome

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

  Inheritance: AD Classification: STRONG, NO_KNOWN Submitted by: G2P, PanelApp Australia
• 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 8 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_001953.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.963

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TYMP	NM_001953.5	MANE Select	c.847C>G	p.His283Asp	missense	Exon 7 of 10	NP_001944.1	E5KRG5
	TYMP	NM_001257989.1		c.847C>G	p.His283Asp	missense	Exon 7 of 10	NP_001244918.1	P19971-2
	TYMP	NM_001113755.3		c.847C>G	p.His283Asp	missense	Exon 7 of 10	NP_001107227.1	E5KRG5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TYMP	ENST00000252029.8	TSL:1 MANE Select	c.847C>G	p.His283Asp	missense	Exon 7 of 10	ENSP00000252029.3	P19971-1
	TYMP	ENST00000395681.6	TSL:1	c.847C>G	p.His283Asp	missense	Exon 7 of 10	ENSP00000379038.1	P19971-2
	TYMP	ENST00000395678.7	TSL:1	c.847C>G	p.His283Asp	missense	Exon 7 of 10	ENSP00000379036.3	P19971-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Mitochondrial DNA depletion syndrome 1 (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Benign	21
DANN	Benign	0.92
DEOGEN2	Uncertain	0.57	D
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.53
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.77	D
MutationAssessor	Benign	1.2	L
PhyloP100		1.4
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.75	N
REVEL	Uncertain	0.64
Sift	Benign	0.041	D
Sift4G	Uncertain	0.032	D
Polyphen		0.15	B
Vest4		0.59
MutPred		0.91		Loss of catalytic residue at L285 (P = 0.1217)
MVP		0.83
MPC		1.3
ClinPred		0.70	D
GERP RS		2.7
PromoterAI		-0.033	Neutral
Varity_R		0.83
gMVP		0.80
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1064792871; hg19: chr22-50965086;