ENST00000395681.6:c.1175G>C

Variant names:

• chr22-50526141-C-G
• rs1064792873
• ENST00000395681.6:c.1175G>C
• TYMP p.Gly392Ala

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The ENST00000395681.6(TYMP):​c.1175G>C​(p.Gly392Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000751 in 1,331,778 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. G392S) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 7.5e-7 (0 hom.)
• Consequence: TYMP ENST00000395681.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.908
• 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: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• Leigh syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• myopia 6

  Inheritance: AD Classification: STRONG, NO_KNOWN Submitted by: PanelApp Australia, 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.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr22-50526142-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 223064.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.95

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000395681.6. 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.1160G>C	p.Gly387Ala	missense splice_region	Exon 9 of 10	NP_001944.1	E5KRG5
	TYMP	NM_001257989.1		c.1175G>C	p.Gly392Ala	missense	Exon 9 of 10	NP_001244918.1	P19971-2
	TYMP	NM_001113755.3		c.1160G>C	p.Gly387Ala	missense splice_region	Exon 9 of 10	NP_001107227.1	E5KRG5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TYMP	ENST00000395681.6	TSL:1	c.1175G>C	p.Gly392Ala	missense	Exon 9 of 10	ENSP00000379038.1	P19971-2
	TYMP	ENST00000252029.8	TSL:1 MANE Select	c.1160G>C	p.Gly387Ala	missense splice_region	Exon 9 of 10	ENSP00000252029.3	P19971-1
	TYMP	ENST00000395678.7	TSL:1	c.1160G>C	p.Gly387Ala	missense splice_region	Exon 9 of 10	ENSP00000379036.3	P19971-1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 7.51e-7 AC: 1 AN: 1331778 Hom.: 0 Cov.: 33 AF XY: 0.00000152 AC XY: 1 AN XY: 656268

African (AFR) AF: 0.00 AC: 0 AN: 26812

American (AMR) AF: 0.00 AC: 0 AN: 29318

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22744

East Asian (EAS) AF: 0.00 AC: 0 AN: 30634

South Asian (SAS) AF: 0.00 AC: 0 AN: 73248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32832

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4630

European-Non Finnish (NFE) AF: 9.47e-7 AC: 1 AN: 1056074

Other (OTH) AF: 0.00 AC: 0 AN: 55486

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.46
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D
Eigen	Uncertain	0.32
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.31	T
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		0.91
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-5.6	D
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
PromoterAI		0.057	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.92
gMVP		0.75
Mutation Taster		=9/91	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1064792873;

hg19: chr22-50964570;