NM_001953.5:c.931G>T

Variant names:

• chr22-50526474-C-A
• rs121913040
• NM_001953.5:c.931G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PM5 PP3_Moderate PP5

The NM_001953.5(TYMP):​c.931G>T​(p.Gly311Cys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000747 in 1,339,048 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G311R) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.5e-7 (0 hom.)
• Consequence: TYMP NM_001953.5 missense, splice_region
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.264
• Publications: 3 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr22-50526474-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 16664.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.907
• PP5: Variant 22-50526474-C-A is Pathogenic according to our data. Variant chr22-50526474-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 223049.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TYMP	NM_001953.5	c.931G>T	p.Gly311Cys	missense_variant, splice_region_variant	Exon 8 of 10	ENST00000252029.8	NP_001944.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TYMP	ENST00000252029.8	c.931G>T	p.Gly311Cys	missense_variant, splice_region_variant	Exon 8 of 10	1	NM_001953.5	ENSP00000252029.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.47e-7 AC: 1 AN: 1339048 Hom.: 0 Cov.: 36 AF XY: 0.00000152 AC XY: 1 AN XY: 658756

African (AFR) AF: 0.00 AC: 0 AN: 27640

American (AMR) AF: 0.00 AC: 0 AN: 28512

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21646

East Asian (EAS) AF: 0.00 AC: 0 AN: 33516

South Asian (SAS) AF: 0.00 AC: 0 AN: 71746

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35552

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4082

European-Non Finnish (NFE) AF: 9.43e-7 AC: 1 AN: 1060706

Other (OTH) AF: 0.00 AC: 0 AN: 55648

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Mitochondrial DNA depletion syndrome 1 Pathogenic:1

Jan 14, 2016

GeneReviews

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D;.;D;D;D
Eigen	Uncertain	0.24
Eigen_PC	Benign	0.022
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.76	.;T;.;T;T
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	M;M;M;M;.
PhyloP100		0.26
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-5.9	D;D;D;D;D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0030	D;D;D;D;D
Sift4G	Uncertain	0.0060	D;D;D;D;D
Polyphen		1.0	D;.;D;D;.
Vest4		0.77
MutPred		0.71		Loss of MoRF binding (P = 0.3564);Loss of MoRF binding (P = 0.3564);Loss of MoRF binding (P = 0.3564);Loss of MoRF binding (P = 0.3564);.;
MVP		0.94
MPC		1.3
ClinPred		0.99	D
GERP RS		2.4
PromoterAI		-0.45	Neutral
Varity_R		0.97
gMVP		0.90
Mutation Taster		=20/80	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: rs121913040; hg19: chr22-50964903;