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:16
• 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), 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 -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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TYMP	NM_001953.5	c.929-6_929-3delCCGC		splice_region_variant, intron_variant	Intron 7 of 9	ENST00000252029.8	NP_001944.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TYMP	ENST00000252029.8	c.929-6_929-3delCCGC		splice_region_variant, intron_variant	Intron 7 of 9	1	NM_001953.5	ENSP00000252029.3

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

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Uncertain:1 Benign:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mitochondrial DNA depletion syndrome 1 Pathogenic:1 Benign:6

Jan 14, 2016

GeneReviews

Significance: Pathogenic

Review Status: flagged submission

Collection Method: literature only

Apr 22, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 06, 2017

Counsyl

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 13, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 04, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

European Non-Finnish population allele frequency is 1.460% (rs201685922, 1045/67956 alleles, 12 homozygotes in gnomAD v3.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.5.1, this variant is classified as BENIGN. Following criteria are met: BA1

not specified Uncertain:1 Benign:4

Jan 07, 2014

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is found in MITONUC-MITOP,MITO24,DEPLTN-MITOP panel(s).

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 16, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

Feb 19, 2016

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 17, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TYMP c.929-6_929-3delCCGC alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.012 in 150776 control chromosomes in the gnomAD database, including 19 homozygotes. The observed variant frequency is approximately 11-fold of the estimated maximal expected allele frequency for a pathogenic variant in TYMP causing Mitochondrial DNA Depletion Syndrome 1 (MNGIE type) phenotype (0.0011), strongly suggesting that the variant is benign. ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign (n=9), as uncertain significance (n=1) and as pathogenic (n=1). Based on the evidence outlined above, the variant was classified as benign.

not provided Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 19, 2015

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TYMP: BP4, BS1, BS2

Mitochondrial neurogastrointestinal encephalomyopathy Benign:1

Dec 26, 2019

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Mitochondrial complex IV deficiency, nuclear type 1 Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Fatal Infantile Cardioencephalomyopathy Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

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;