rs946234163

Variant names:

• chr22-50526639-C-T
• rs946234163
• NM_001953.5:c.865G>A

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_001953.5(TYMP):​c.865G>A​(p.Glu289Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000282 in 1,417,480 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E289A) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: TYMP NM_001953.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2
• Conservation: PhyloP100: 3.28
• Publications: 1 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), PanelApp Australia, G2P
• Leigh syndrome

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

  Inheritance: AD Classification: STRONG, NO_KNOWN Submitted by: G2P, PanelApp Australia
• autosomal recessive axonal charcot-marie-tooth disease due to copper metabolism defect

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_001953.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr22-50526638-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 16653.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984
• PP5: Variant 22-50526639-C-T is Pathogenic according to our data. Variant chr22-50526639-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 223044.

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.865G>A	p.Glu289Lys	missense	Exon 7 of 10	NP_001944.1	E5KRG5
	TYMP	NM_001257989.1		c.865G>A	p.Glu289Lys	missense	Exon 7 of 10	NP_001244918.1	P19971-2
	TYMP	NM_001113755.3		c.865G>A	p.Glu289Lys	missense	Exon 7 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.865G>A	p.Glu289Lys	missense	Exon 7 of 10	ENSP00000252029.3	P19971-1
	TYMP	ENST00000395681.6	TSL:1	c.865G>A	p.Glu289Lys	missense	Exon 7 of 10	ENSP00000379038.1	P19971-2
	TYMP	ENST00000395678.7	TSL:1	c.865G>A	p.Glu289Lys	missense	Exon 7 of 10	ENSP00000379036.3	P19971-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000594 AC: 1 AN: 168488 AF XY: 0.0000109

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: 0.0000148

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000282 AC: 4 AN: 1417480 Hom.: 0 Cov.: 36 AF XY: 0.00000428 AC XY: 3 AN XY: 701564

African (AFR) AF: 0.00 AC: 0 AN: 32484

American (AMR) AF: 0.00 AC: 0 AN: 39244

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25358

East Asian (EAS) AF: 0.00 AC: 0 AN: 37262

South Asian (SAS) AF: 0.0000123 AC: 1 AN: 81070

European-Finnish (FIN) AF: 0.0000216 AC: 1 AN: 46250

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5706

European-Non Finnish (NFE) AF: 0.00000183 AC: 2 AN: 1091342

Other (OTH) AF: 0.00 AC: 0 AN: 58764

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	-	-	Mitochondrial DNA depletion syndrome 1 (2)
-	1	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.91	D
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.0	H
PhyloP100		3.3
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.5	D
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.012	D
Polyphen		1.0	D
Vest4		0.74
MutPred		0.95		Gain of ubiquitination at E289 (P = 0.0211)
MVP		0.98
MPC		1.4
ClinPred		1.0	D
GERP RS		4.8
PromoterAI		-0.052	Neutral
Varity_R		0.95
gMVP		0.96
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: rs946234163; hg19: chr22-50965068;