chr22-50526017-A-T

Variant names:

• chr22-50526017-A-T
• rs1138404
• NM_001953.5:c.1284T>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001953.5(TYMP):​c.1284T>A​(p.Gly428Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.111 in 1,470,092 control chromosomes in the GnomAD database, including 10,217 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G428G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.14 (1824 hom., cov: 34)
  • Exomes 𝑓: 0.11 (8393 hom.)
• Consequence: TYMP NM_001953.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.412
• Publications: 19 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 22-50526017-A-T is Benign according to our data. Variant chr22-50526017-A-T is described in ClinVar as Benign. ClinVar VariationId is 137876.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.412 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.227 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.1284T>A	p.Gly428Gly	synonymous	Exon 9 of 10	NP_001944.1
	TYMP	NM_001257989.1		c.1299T>A	p.Gly433Gly	synonymous	Exon 9 of 10	NP_001244918.1
	TYMP	NM_001113755.3		c.1284T>A	p.Gly428Gly	synonymous	Exon 9 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.1284T>A	p.Gly428Gly	synonymous	Exon 9 of 10	ENSP00000252029.3
	TYMP	ENST00000395681.6	TSL:1	c.1299T>A	p.Gly433Gly	synonymous	Exon 9 of 10	ENSP00000379038.1
	TYMP	ENST00000395678.7	TSL:1	c.1284T>A	p.Gly428Gly	synonymous	Exon 9 of 10	ENSP00000379036.3

Frequencies

GnomAD3 genomes AF: 0.141 AC: 21351 AN: 151770 Hom.: 1819 Cov.: 34

Gnomad AFR AF: 0.231

Gnomad AMI AF: 0.0165

Gnomad AMR AF: 0.160

Gnomad ASJ AF: 0.0937

Gnomad EAS AF: 0.0971

Gnomad SAS AF: 0.178

Gnomad FIN AF: 0.0469

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.101

Gnomad OTH AF: 0.133

GnomAD2 exomes AF: 0.112 AC: 8689 AN: 77894 AF XY: 0.117

Gnomad AFR exome AF: 0.218

Gnomad AMR exome AF: 0.114

Gnomad ASJ exome AF: 0.0905

Gnomad EAS exome AF: 0.0817

Gnomad FIN exome AF: 0.0480

Gnomad NFE exome AF: 0.0969

Gnomad OTH exome AF: 0.105

GnomAD4 exome AF: 0.108 AC: 142497 AN: 1318212 Hom.: 8393 Cov.: 35 AF XY: 0.110 AC XY: 71220 AN XY: 650016

African (AFR) AF: 0.241 AC: 6351 AN: 26322

American (AMR) AF: 0.124 AC: 3306 AN: 26564

Ashkenazi Jewish (ASJ) AF: 0.0955 AC: 2190 AN: 22926

East Asian (EAS) AF: 0.108 AC: 3102 AN: 28846

South Asian (SAS) AF: 0.172 AC: 12463 AN: 72368

European-Finnish (FIN) AF: 0.0530 AC: 1742 AN: 32898

Middle Eastern (MID) AF: 0.112 AC: 441 AN: 3954

European-Non Finnish (NFE) AF: 0.102 AC: 106562 AN: 1049736

Other (OTH) AF: 0.116 AC: 6340 AN: 54598

GnomAD4 genome AF: 0.141 AC: 21372 AN: 151880 Hom.: 1824 Cov.: 34 AF XY: 0.140 AC XY: 10371 AN XY: 74286

African (AFR) AF: 0.231 AC: 9558 AN: 41428

American (AMR) AF: 0.160 AC: 2436 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.0937 AC: 325 AN: 3470

East Asian (EAS) AF: 0.0972 AC: 500 AN: 5146

South Asian (SAS) AF: 0.177 AC: 853 AN: 4820

European-Finnish (FIN) AF: 0.0469 AC: 495 AN: 10550

Middle Eastern (MID) AF: 0.0993 AC: 29 AN: 292

European-Non Finnish (NFE) AF: 0.101 AC: 6879 AN: 67886

Other (OTH) AF: 0.134 AC: 282 AN: 2110

Alfa AF: 0.119 Hom.: 179

Bravo AF: 0.151

Asia WGS AF: 0.155 AC: 532 AN: 3450

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	2	Mitochondrial DNA depletion syndrome 1 (2)
-	-	1	Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 1 (1)
-	-	1	Mitochondrial complex IV deficiency, nuclear type 1 (1)
-	-	1	Mitochondrial neurogastrointestinal encephalomyopathy (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	6.1
DANN	Benign	0.67
PhyloP100		-0.41
PromoterAI		0.022	Neutral
Mutation Taster		=296/4	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: rs1138404; hg19: chr22-50964446; COSMIC: COSV105821447;