chr22-50525787-G-C

Variant names:

• chr22-50525787-G-C
• rs3202236
• NM_001953.5:c.1432C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001953.5(TYMP):​c.1432C>G​(p.Leu478Val) 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 benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L478L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 35)
• Consequence: TYMP NM_001953.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.257
• Publications: 3 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18982321).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TYMP	NM_001953.5	c.1432C>G	p.Leu478Val	missense_variant	Exon 10 of 10	ENST00000252029.8	NP_001944.1
SCO2	NM_005138.3	c.-329C>G		upstream_gene_variant		ENST00000395693.8	NP_005129.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TYMP	ENST00000252029.8	c.1432C>G	p.Leu478Val	missense_variant	Exon 10 of 10	1	NM_001953.5	ENSP00000252029.3
SCO2	ENST00000395693.8	c.-329C>G		upstream_gene_variant		1	NM_005138.3	ENSP00000379046.4

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome Cov.: 39

GnomAD4 genome Cov.: 35

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.085	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	12
DANN	Benign	0.97
DEOGEN2	Benign	0.20	T;.;T;T;T
Eigen	Benign	-0.92
Eigen_PC	Benign	-1.0
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.46	.;T;.;T;T
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.14	T;T;T;T;T
MetaSVM	Uncertain	0.12	D
MutationAssessor	Uncertain	2.3	M;.;M;M;.
PhyloP100		-0.26
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.45	N;N;N;N;N
REVEL	Benign	0.26
Sift	Uncertain	0.027	D;D;D;D;D
Sift4G	Uncertain	0.039	D;D;D;D;T
Polyphen		0.64	P;.;P;P;.
Vest4		0.22
MutPred		0.13		Gain of sheet (P = 0.0477);.;Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);.;
MVP		0.67
MPC		0.64
ClinPred		0.15	T
GERP RS		0.13
PromoterAI		-0.042	Neutral
Varity_R		0.17
gMVP		0.34
Mutation Taster		=91/9	polymorphism

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: rs3202236; hg19: chr22-50964216;