chr22-50526278-C-G

Variant names:

• chr22-50526278-C-G
• rs765007158
• NM_001953.5:c.1127G>C

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.1127G>C​(p.Arg376Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000718 in 1,392,852 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R376Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: TYMP NM_001953.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.17
• 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=0.12140989).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TYMP	NM_001953.5	MANE Select	c.1127G>C	p.Arg376Pro	missense	Exon 8 of 10	NP_001944.1
	TYMP	NM_001257989.1		c.1127G>C	p.Arg376Pro	missense	Exon 8 of 10	NP_001244918.1
	TYMP	NM_001113755.3		c.1127G>C	p.Arg376Pro	missense	Exon 8 of 10	NP_001107227.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TYMP	ENST00000252029.8	TSL:1 MANE Select	c.1127G>C	p.Arg376Pro	missense	Exon 8 of 10	ENSP00000252029.3
	TYMP	ENST00000395681.6	TSL:1	c.1127G>C	p.Arg376Pro	missense	Exon 8 of 10	ENSP00000379038.1
	TYMP	ENST00000395678.7	TSL:1	c.1127G>C	p.Arg376Pro	missense	Exon 8 of 10	ENSP00000379036.3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 7.18e-7 AC: 1 AN: 1392852 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 689804

African (AFR) AF: 0.00 AC: 0 AN: 29368

American (AMR) AF: 0.00 AC: 0 AN: 38268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24650

East Asian (EAS) AF: 0.00 AC: 0 AN: 34746

South Asian (SAS) AF: 0.00 AC: 0 AN: 79614

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34818

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5314

European-Non Finnish (NFE) AF: 9.19e-7 AC: 1 AN: 1088076

Other (OTH) AF: 0.00 AC: 0 AN: 57998

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.065	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	4.7
DANN	Benign	0.78
DEOGEN2	Benign	0.19	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.31	T
M_CAP	Pathogenic	0.81	D
MetaRNN	Benign	0.12	T
MetaSVM	Uncertain	0.0084	D
MutationAssessor	Benign	0.72	N
PhyloP100		-1.2
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.87	N
REVEL	Benign	0.17
Sift	Benign	0.26	T
Sift4G	Benign	0.48	T
Polyphen		0.0010	B
Vest4		0.17
MutPred		0.25		Gain of glycosylation at R376 (P = 0.0375)
MVP		0.35
MPC		0.64
ClinPred		0.075	T
GERP RS		-6.6
PromoterAI		-0.0052	Neutral
Varity_R		0.67
gMVP		0.50
Mutation Taster		=78/22	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: rs765007158; hg19: chr22-50964707;