22-50525826-C-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001953.5(TYMP):​c.1393G>A​(p.Ala465Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0498 in 1,609,694 control chromosomes in the GnomAD database, including 2,263 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A465S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.039 (145 hom., cov: 34)
  • Exomes 𝑓: 0.051 (2118 hom.)
• Consequence: TYMP NM_001953.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.495
• Publications: 27 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017577708).
• BP6: Variant 22-50525826-C-T is Benign according to our data. Variant chr22-50525826-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 137878.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0528 is higher than 0.05.

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.1393G>A	p.Ala465Thr	missense	Exon 10 of 10	NP_001944.1
	TYMP	NM_001257989.1		c.1408G>A	p.Ala470Thr	missense	Exon 10 of 10	NP_001244918.1
	TYMP	NM_001113755.3		c.1393G>A	p.Ala465Thr	missense	Exon 10 of 10	NP_001107227.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TYMP	ENST00000252029.8	TSL:1 MANE Select	c.1393G>A	p.Ala465Thr	missense	Exon 10 of 10	ENSP00000252029.3
	TYMP	ENST00000395681.6	TSL:1	c.1408G>A	p.Ala470Thr	missense	Exon 10 of 10	ENSP00000379038.1
	TYMP	ENST00000395678.7	TSL:1	c.1393G>A	p.Ala465Thr	missense	Exon 10 of 10	ENSP00000379036.3

Frequencies

GnomAD3 genomes AF: 0.0395 AC: 6011 AN: 152196 Hom.: 145 Cov.: 34

Gnomad AFR AF: 0.0107

Gnomad AMI AF: 0.0482

Gnomad AMR AF: 0.0345

Gnomad ASJ AF: 0.0885

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.0513

Gnomad FIN AF: 0.0588

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.0542

Gnomad OTH AF: 0.0406

GnomAD2 exomes AF: 0.0459 AC: 10439 AN: 227524 AF XY: 0.0483

Gnomad AFR exome AF: 0.00963

Gnomad AMR exome AF: 0.0275

Gnomad ASJ exome AF: 0.0855

Gnomad EAS exome AF: 0.000172

Gnomad FIN exome AF: 0.0584

Gnomad NFE exome AF: 0.0541

Gnomad OTH exome AF: 0.0544

GnomAD4 exome AF: 0.0508 AC: 74101 AN: 1457384 Hom.: 2118 Cov.: 37 AF XY: 0.0518 AC XY: 37532 AN XY: 724990

African (AFR) AF: 0.00980 AC: 327 AN: 33374

American (AMR) AF: 0.0289 AC: 1287 AN: 44476

Ashkenazi Jewish (ASJ) AF: 0.0872 AC: 2270 AN: 26040

East Asian (EAS) AF: 0.000177 AC: 7 AN: 39578

South Asian (SAS) AF: 0.0600 AC: 5169 AN: 86118

European-Finnish (FIN) AF: 0.0584 AC: 3006 AN: 51480

Middle Eastern (MID) AF: 0.103 AC: 583 AN: 5666

European-Non Finnish (NFE) AF: 0.0527 AC: 58488 AN: 1110558

Other (OTH) AF: 0.0493 AC: 2964 AN: 60094

GnomAD4 genome AF: 0.0395 AC: 6012 AN: 152310 Hom.: 145 Cov.: 34 AF XY: 0.0403 AC XY: 3002 AN XY: 74476

African (AFR) AF: 0.0107 AC: 443 AN: 41576

American (AMR) AF: 0.0344 AC: 527 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0885 AC: 307 AN: 3470

East Asian (EAS) AF: 0.000772 AC: 4 AN: 5180

South Asian (SAS) AF: 0.0519 AC: 251 AN: 4834

European-Finnish (FIN) AF: 0.0588 AC: 624 AN: 10616

Middle Eastern (MID) AF: 0.130 AC: 38 AN: 292

European-Non Finnish (NFE) AF: 0.0542 AC: 3689 AN: 68008

Other (OTH) AF: 0.0402 AC: 85 AN: 2116

Alfa AF: 0.0424 Hom.: 101

Bravo AF: 0.0364

TwinsUK AF: 0.0585 AC: 217

ALSPAC AF: 0.0457 AC: 176

ESP6500AA AF: 0.0114 AC: 47

ESP6500EA AF: 0.0513 AC: 417

ExAC AF: 0.0441 AC: 5184

Asia WGS AF: 0.0210 AC: 74 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	3	Mitochondrial DNA depletion syndrome 1 (3)
-	-	2	not specified (2)
-	-	1	Fatal Infantile Cardioencephalomyopathy (1)
-	-	1	Mitochondrial neurogastrointestinal encephalomyopathy (1)
-	-	1	TYMP-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	17
DANN	Benign	0.96
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.75
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.54	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.8	L
PhyloP100		-0.49
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.14	N
REVEL	Benign	0.23
Sift	Benign	0.24	T
Sift4G	Benign	0.31	T
Polyphen		0.14	B
Vest4		0.055
MPC		0.45
ClinPred		0.014	T
GERP RS		2.3
PromoterAI		0.040	Neutral
Varity_R		0.17
gMVP		0.34
Mutation Taster		=100/0	polymorphism (auto)

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: rs112723255; hg19: chr22-50964255; COSMIC: COSV52687812; COSMIC: COSV52687812;