rs1060499533

Variant names:

• chr22-50526293-A-G
• rs1060499533
• NM_001953.5:c.1112T>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001953.5(TYMP):​c.1112T>C​(p.Leu371Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000713 in 1,402,028 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. L371L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: TYMP NM_001953.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 2.66
• Publications: 2 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: G2P, Labcorp Genetics (formerly Invitae)
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.765

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.1112T>C	p.Leu371Pro	missense	Exon 8 of 10	NP_001944.1	E5KRG5
	TYMP	NM_001257989.1		c.1112T>C	p.Leu371Pro	missense	Exon 8 of 10	NP_001244918.1	P19971-2
	TYMP	NM_001113755.3		c.1112T>C	p.Leu371Pro	missense	Exon 8 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.1112T>C	p.Leu371Pro	missense	Exon 8 of 10	ENSP00000252029.3	P19971-1
	TYMP	ENST00000395681.6	TSL:1	c.1112T>C	p.Leu371Pro	missense	Exon 8 of 10	ENSP00000379038.1	P19971-2
	TYMP	ENST00000395678.7	TSL:1	c.1112T>C	p.Leu371Pro	missense	Exon 8 of 10	ENSP00000379036.3	P19971-1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00 AC: 0 AN: 165974 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.13e-7 AC: 1 AN: 1402028 Hom.: 0 Cov.: 33 AF XY: 0.00000144 AC XY: 1 AN XY: 695232

African (AFR) AF: 0.00 AC: 0 AN: 29650

American (AMR) AF: 0.00 AC: 0 AN: 39874

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24900

East Asian (EAS) AF: 0.00 AC: 0 AN: 35428

South Asian (SAS) AF: 0.00 AC: 0 AN: 80670

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35314

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5246

European-Non Finnish (NFE) AF: 9.15e-7 AC: 1 AN: 1092642

Other (OTH) AF: 0.00 AC: 0 AN: 58304

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions as Germline

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	Uncertain	0.39
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.55	D
Eigen	Benign	0.12
Eigen_PC	Benign	0.092
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.42	T
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Uncertain	0.65	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		2.7
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-2.5	D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0060	D
Sift4G	Benign	0.13	T
Polyphen		1.0	D
Vest4		0.67
MutPred		0.68		Loss of stability (P = 0.0881)
MVP		0.88
MPC		1.6
ClinPred		0.97	D
GERP RS		3.3
PromoterAI		0.087	Neutral
Varity_R		0.90
gMVP		0.74
Mutation Taster		=0/100	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: rs1060499533; hg19: chr22-50964722;