chr22-50526657-G-C

Variant names:

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

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), 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 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TYMP	NM_001953.5	c.847C>G	p.His283Asp	missense_variant	Exon 7 of 10	ENST00000252029.8	NP_001944.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TYMP	ENST00000252029.8	c.847C>G	p.His283Asp	missense_variant	Exon 7 of 10	1	NM_001953.5	ENSP00000252029.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

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

- -

not provided Uncertain:1

Sep 07, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces histidine, which is basic and polar, with aspartic acid, which is acidic and polar, at codon 283 of the TYMP protein (p.His283Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with mitochondrial neurogastrointestinal encephalomyopathy with other rare variant(s) present on the same allele (PMID: 15505189). ClinVar contains an entry for this variant (Variation ID: 223041). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TYMP protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

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;.;D;D;D
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.53
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	.;D;.;T;T
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D
MetaSVM	Uncertain	0.77	D
MutationAssessor	Benign	1.2	L;L;L;L;.
PhyloP100		1.4
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.75	N;N;N;N;N
REVEL	Uncertain	0.64
Sift	Benign	0.041	D;D;D;D;D
Sift4G	Uncertain	0.032	D;D;D;D;D
Polyphen		0.15	B;.;B;B;.
Vest4		0.59
MutPred		0.91		Loss of catalytic residue at L285 (P = 0.1217);Loss of catalytic residue at L285 (P = 0.1217);Loss of catalytic residue at L285 (P = 0.1217);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;