22-50525818-G-T

Variant names:

• chr22-50525818-G-T
• rs1061205
• NM_001953.5:c.1401C>A

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.1401C>A​(p.Phe467Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,988 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. F467F) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TYMP NM_001953.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.562
• 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: 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=0.11600965).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TYMP	NM_001953.5	c.1401C>A	p.Phe467Leu	missense_variant	Exon 10 of 10	ENST00000252029.8	NP_001944.1
SCO2	NM_005138.3	c.-360C>A		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.1401C>A	p.Phe467Leu	missense_variant	Exon 10 of 10	1	NM_001953.5	ENSP00000252029.3
SCO2	ENST00000395693.8	c.-360C>A		upstream_gene_variant		1	NM_005138.3	ENSP00000379046.4

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457988 Hom.: 0 Cov.: 37 AF XY: 0.00 AC XY: 0 AN XY: 725302

African (AFR) AF: 0.00 AC: 0 AN: 33382

American (AMR) AF: 0.00 AC: 0 AN: 44568

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26052

East Asian (EAS) AF: 0.00 AC: 0 AN: 39600

South Asian (SAS) AF: 0.00 AC: 0 AN: 86154

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51556

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5710

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1110852

Other (OTH) AF: 0.00 AC: 0 AN: 60114

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Uncertain	0.098	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	17
DANN	Benign	0.82
DEOGEN2	Benign	0.21	T;.;T;T;T
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.90
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.47	.;T;.;T;T
M_CAP	Uncertain	0.25	D
MetaRNN	Benign	0.12	T;T;T;T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.8	L;.;L;L;.
PhyloP100		-0.56
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.020	N;N;N;N;N
REVEL	Uncertain	0.46
Sift	Benign	0.70	T;T;T;T;T
Sift4G	Benign	0.65	T;T;T;T;T
Polyphen		0.029	B;.;B;B;.
Vest4		0.20
MutPred		0.20		Gain of glycosylation at S462 (P = 0.1356);.;Gain of glycosylation at S462 (P = 0.1356);Gain of glycosylation at S462 (P = 0.1356);.;
MVP		0.71
MPC		0.52
ClinPred		0.071	T
GERP RS		2.3
PromoterAI		0.055	Neutral
Varity_R		0.29
gMVP		0.48
Mutation Taster		=0/100	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1061205; hg19: chr22-50964247;