22-50526673-C-T

Variant names:

• chr22-50526673-C-T
• rs8141558
• NM_001953.5:c.831G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001953.5(TYMP):​c.831G>A​(p.Leu277Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00644 in 1,551,898 control chromosomes in the GnomAD database, including 453 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L277L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.032 (235 hom., cov: 33)
  • Exomes 𝑓: 0.0037 (218 hom.)
• Consequence: TYMP NM_001953.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.729
• 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), 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: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 22-50526673-C-T is Benign according to our data. Variant chr22-50526673-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 137873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.729 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.106 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.831G>A	p.Leu277Leu	synonymous	Exon 7 of 10	NP_001944.1	E5KRG5
	TYMP	NM_001257989.1		c.831G>A	p.Leu277Leu	synonymous	Exon 7 of 10	NP_001244918.1	P19971-2
	TYMP	NM_001113755.3		c.831G>A	p.Leu277Leu	synonymous	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.831G>A	p.Leu277Leu	synonymous	Exon 7 of 10	ENSP00000252029.3	P19971-1
	TYMP	ENST00000395681.6	TSL:1	c.831G>A	p.Leu277Leu	synonymous	Exon 7 of 10	ENSP00000379038.1	P19971-2
	TYMP	ENST00000395678.7	TSL:1	c.831G>A	p.Leu277Leu	synonymous	Exon 7 of 10	ENSP00000379036.3	P19971-1

Frequencies

GnomAD3 genomes AF: 0.0320 AC: 4866 AN: 152230 Hom.: 233 Cov.: 33

Gnomad AFR AF: 0.108

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0165

Gnomad ASJ AF: 0.00662

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.000603

Gnomad OTH AF: 0.0225

GnomAD2 exomes AF: 0.00832 AC: 1221 AN: 146814 AF XY: 0.00647

Gnomad AFR exome AF: 0.116

Gnomad AMR exome AF: 0.00631

Gnomad ASJ exome AF: 0.00946

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000745

Gnomad OTH exome AF: 0.00640

GnomAD4 exome AF: 0.00366 AC: 5117 AN: 1399550 Hom.: 218 Cov.: 36 AF XY: 0.00324 AC XY: 2242 AN XY: 691454

African (AFR) AF: 0.110 AC: 3504 AN: 31982

American (AMR) AF: 0.00812 AC: 299 AN: 36818

Ashkenazi Jewish (ASJ) AF: 0.00825 AC: 208 AN: 25200

East Asian (EAS) AF: 0.00 AC: 0 AN: 36320

South Asian (SAS) AF: 0.000200 AC: 16 AN: 79902

European-Finnish (FIN) AF: 0.0000238 AC: 1 AN: 42008

Middle Eastern (MID) AF: 0.00916 AC: 52 AN: 5676

European-Non Finnish (NFE) AF: 0.000464 AC: 503 AN: 1083464

Other (OTH) AF: 0.00918 AC: 534 AN: 58180

GnomAD4 genome AF: 0.0320 AC: 4872 AN: 152348 Hom.: 235 Cov.: 33 AF XY: 0.0314 AC XY: 2336 AN XY: 74504

African (AFR) AF: 0.108 AC: 4499 AN: 41578

American (AMR) AF: 0.0165 AC: 253 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00662 AC: 23 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.000603 AC: 41 AN: 68034

Other (OTH) AF: 0.0223 AC: 47 AN: 2110

Alfa AF: 0.0223 Hom.: 25

Bravo AF: 0.0365

Asia WGS AF: 0.00808 AC: 28 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)
-	-	1	Fatal Infantile Cardioencephalomyopathy (1)
-	-	1	Mitochondrial complex IV deficiency, nuclear type 1 (1)
-	-	1	Mitochondrial DNA depletion syndrome 1 (1)
-	-	1	Mitochondrial neurogastrointestinal encephalomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_noAF	Benign	-0.34
CADD	Benign	15
DANN	Benign	0.93
PhyloP100		0.73
PromoterAI		0.035	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs8141558; hg19: chr22-50965102;