NM_001953.5:c.1393G>T

Variant names:

• chr22-50525826-C-A
• rs112723255
• NM_001953.5:c.1393G>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001953.5(TYMP):​c.1393G>T​(p.Ala465Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,204 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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. A465T) has been classified as Benign.

• Frequency: Genomes: 𝑓 0.000013 (0 hom., cov: 34)
• Consequence: TYMP NM_001953.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.495

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16823846).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TYMP	NM_001953.5	c.1393G>T	p.Ala465Ser	missense_variant	Exon 10 of 10	ENST00000252029.8	NP_001944.1
SCO2	NM_005138.3	c.-368G>T		upstream_gene_variant		ENST00000395693.8	NP_005129.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TYMP	ENST00000252029.8	c.1393G>T	p.Ala465Ser	missense_variant	Exon 10 of 10	1	NM_001953.5	ENSP00000252029.3
SCO2	ENST00000395693.8	c.-368G>T		upstream_gene_variant		1	NM_005138.3	ENSP00000379046.4

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152204 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 37

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152204 Hom.: 0 Cov.: 34 AF XY: 0.0000269 AC XY: 2 AN XY: 74354

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.070	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	15
DANN	Benign	0.80
DEOGEN2	Benign	0.16	T;.;T;T;T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.78
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.50	.;T;.;T;T
M_CAP	Pathogenic	0.68	D
MetaRNN	Benign	0.17	T;T;T;T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	1.8	L;.;L;L;.
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	0.020	N;N;N;N;N
REVEL	Benign	0.20
Sift	Benign	0.31	T;T;T;T;T
Sift4G	Benign	0.34	T;T;T;T;T
Polyphen		0.0080	B;.;B;B;.
Vest4		0.095
MutPred		0.27		Gain of phosphorylation at A465 (P = 0.0134);.;Gain of phosphorylation at A465 (P = 0.0134);Gain of phosphorylation at A465 (P = 0.0134);.;
MVP		0.65
MPC		0.43
ClinPred		0.12	T
GERP RS		2.3
Varity_R		0.20
gMVP		0.33

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

Publications

LitVar

Other links and lift over

dbSNP: rs112723255; hg19: chr22-50964255;