rs201685922

Variant names:

• chr22-50526478-TGCGG-T
• rs201685922
• NM_001953.5:c.929-6_929-3delCCGC

Your query was ambiguous. Multiple possible variants found:

• chr22-50526478-TGCGG-T
• chr22-50526478-TGCGG-TGCGGGCGG

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001953.5(TYMP):​c.929-6_929-3delCCGC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0146 in 1,491,330 control chromosomes in the GnomAD database, including 223 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (20 hom., cov: 33)
  • Exomes 𝑓: 0.015 (203 hom.)
• Consequence: TYMP NM_001953.5 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 U:1 B:17
• Conservation: PhyloP100: 0.298
• Publications: 1 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 -16 ACMG points.

• BP6: Variant 22-50526478-TGCGG-T is Benign according to our data. Variant chr22-50526478-TGCGG-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 215324.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0124 (1884/152112) while in subpopulation NFE AF = 0.0154 (1044/67948). AF 95% confidence interval is 0.0146. There are 20 homozygotes in GnomAd4. There are 984 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 20 AR gene

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.929-6_929-3delCCGC		splice_region intron	N/A	NP_001944.1	E5KRG5
	TYMP	NM_001257989.1		c.929-6_929-3delCCGC		splice_region intron	N/A	NP_001244918.1	P19971-2
	TYMP	NM_001113755.3		c.929-6_929-3delCCGC		splice_region intron	N/A	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.929-6_929-3delCCGC		splice_region intron	N/A	ENSP00000252029.3	P19971-1
	TYMP	ENST00000395681.6	TSL:1	c.929-6_929-3delCCGC		splice_region intron	N/A	ENSP00000379038.1	P19971-2
	TYMP	ENST00000395678.7	TSL:1	c.929-6_929-3delCCGC		splice_region intron	N/A	ENSP00000379036.3	P19971-1

Frequencies

GnomAD3 genomes AF: 0.0124 AC: 1885 AN: 152002 Hom.: 20 Cov.: 33

Gnomad AFR AF: 0.00249

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.0117

Gnomad ASJ AF: 0.0159

Gnomad EAS AF: 0.000387

Gnomad SAS AF: 0.0106

Gnomad FIN AF: 0.0407

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0154

Gnomad OTH AF: 0.00574

GnomAD2 exomes AF: 0.0135 AC: 1148 AN: 85026 AF XY: 0.0137

Gnomad AFR exome AF: 0.00269

Gnomad AMR exome AF: 0.00982

Gnomad ASJ exome AF: 0.0209

Gnomad EAS exome AF: 0.000278

Gnomad FIN exome AF: 0.0412

Gnomad NFE exome AF: 0.0150

Gnomad OTH exome AF: 0.0135

GnomAD4 exome AF: 0.0149 AC: 19959 AN: 1339218 Hom.: 203 AF XY: 0.0148 AC XY: 9770 AN XY: 658708

African (AFR) AF: 0.00217 AC: 60 AN: 27642

American (AMR) AF: 0.00931 AC: 265 AN: 28476

Ashkenazi Jewish (ASJ) AF: 0.0189 AC: 410 AN: 21646

East Asian (EAS) AF: 0.0000896 AC: 3 AN: 33496

South Asian (SAS) AF: 0.0112 AC: 807 AN: 71738

European-Finnish (FIN) AF: 0.0401 AC: 1442 AN: 35944

Middle Eastern (MID) AF: 0.00534 AC: 22 AN: 4116

European-Non Finnish (NFE) AF: 0.0152 AC: 16158 AN: 1060524

Other (OTH) AF: 0.0142 AC: 792 AN: 55636

GnomAD4 genome AF: 0.0124 AC: 1884 AN: 152112 Hom.: 20 Cov.: 33 AF XY: 0.0132 AC XY: 984 AN XY: 74358

African (AFR) AF: 0.00248 AC: 103 AN: 41508

American (AMR) AF: 0.0116 AC: 178 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0159 AC: 55 AN: 3468

East Asian (EAS) AF: 0.000388 AC: 2 AN: 5150

South Asian (SAS) AF: 0.0106 AC: 51 AN: 4830

European-Finnish (FIN) AF: 0.0407 AC: 431 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0154 AC: 1044 AN: 67948

Other (OTH) AF: 0.00568 AC: 12 AN: 2114

Alfa AF: 0.0138 Hom.: 4

Bravo AF: 0.00981

Asia WGS AF: 0.00578 AC: 20 AN: 3472

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	6	Mitochondrial DNA depletion syndrome 1 (7)
-	1	5	not specified (6)
-	-	3	not provided (3)
-	-	1	Fatal Infantile Cardioencephalomyopathy (1)
-	-	1	Mitochondrial complex IV deficiency, nuclear type 1 (1)
-	-	1	Mitochondrial neurogastrointestinal encephalomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.30
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs201685922; hg19: chr22-50964907;