rs131804

Variant names:

• chr22-50526433-G-A
• rs131804
• NM_001953.5:c.972C>T

Your query was ambiguous. Multiple possible variants found:

• chr22-50526433-G-A
• chr22-50526433-G-C
• chr22-50526433-G-T

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.972C>T​(p.Ala324Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.568 in 1,505,476 control chromosomes in the GnomAD database, including 246,359 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. A324A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.52 (21525 hom., cov: 35)
  • Exomes 𝑓: 0.57 (224834 hom.)
• Consequence: TYMP NM_001953.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -0.627
• Publications: 42 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=-0.8).
• BP6: Variant 22-50526433-G-A is Benign according to our data. Variant chr22-50526433-G-A is described in ClinVar as Benign. ClinVar VariationId is 130694.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.627 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.68 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TYMP	NM_001953.5	c.972C>T	p.Ala324Ala	synonymous_variant	Exon 8 of 10	ENST00000252029.8	NP_001944.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TYMP	ENST00000252029.8	c.972C>T	p.Ala324Ala	synonymous_variant	Exon 8 of 10	1	NM_001953.5	ENSP00000252029.3

Frequencies

GnomAD3 genomes AF: 0.520 AC: 79038 AN: 151946 Hom.: 21534 Cov.: 35

Gnomad AFR AF: 0.349

Gnomad AMI AF: 0.595

Gnomad AMR AF: 0.576

Gnomad ASJ AF: 0.570

Gnomad EAS AF: 0.699

Gnomad SAS AF: 0.634

Gnomad FIN AF: 0.637

Gnomad MID AF: 0.596

Gnomad NFE AF: 0.568

Gnomad OTH AF: 0.517

GnomAD2 exomes AF: 0.611 AC: 63060 AN: 103254 AF XY: 0.612

Gnomad AFR exome AF: 0.368

Gnomad AMR exome AF: 0.618

Gnomad ASJ exome AF: 0.572

Gnomad EAS exome AF: 0.713

Gnomad FIN exome AF: 0.631

Gnomad NFE exome AF: 0.587

Gnomad OTH exome AF: 0.600

GnomAD4 exome AF: 0.574 AC: 776735 AN: 1353422 Hom.: 224834 Cov.: 61 AF XY: 0.576 AC XY: 384597 AN XY: 667804

African (AFR) AF: 0.334 AC: 9203 AN: 27518

American (AMR) AF: 0.612 AC: 19622 AN: 32072

Ashkenazi Jewish (ASJ) AF: 0.557 AC: 12871 AN: 23088

East Asian (EAS) AF: 0.711 AC: 23283 AN: 32744

South Asian (SAS) AF: 0.645 AC: 48465 AN: 75194

European-Finnish (FIN) AF: 0.614 AC: 21035 AN: 34234

Middle Eastern (MID) AF: 0.578 AC: 2370 AN: 4102

European-Non Finnish (NFE) AF: 0.570 AC: 608435 AN: 1068142

Other (OTH) AF: 0.558 AC: 31451 AN: 56328

GnomAD4 genome AF: 0.520 AC: 79041 AN: 152054 Hom.: 21525 Cov.: 35 AF XY: 0.529 AC XY: 39312 AN XY: 74332

African (AFR) AF: 0.349 AC: 14494 AN: 41520

American (AMR) AF: 0.576 AC: 8797 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.570 AC: 1977 AN: 3466

East Asian (EAS) AF: 0.699 AC: 3597 AN: 5148

South Asian (SAS) AF: 0.633 AC: 3057 AN: 4832

European-Finnish (FIN) AF: 0.637 AC: 6745 AN: 10590

Middle Eastern (MID) AF: 0.586 AC: 171 AN: 292

European-Non Finnish (NFE) AF: 0.568 AC: 38577 AN: 67908

Other (OTH) AF: 0.514 AC: 1087 AN: 2114

Alfa AF: 0.534 Hom.: 3869

Bravo AF: 0.509

Asia WGS AF: 0.579 AC: 2006 AN: 3462

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 10, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 30, 2011

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:4

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 22, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mitochondrial DNA depletion syndrome 1 Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Spinal muscular atrophy Benign:1

Sep 16, 2020

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: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Fatal Infantile Cardioencephalomyopathy Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_noAF	Benign	-0.80
CADD	Benign	6.2
DANN	Benign	0.94
PhyloP100		-0.63
PromoterAI		-0.13	Neutral
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: rs131804; hg19: chr22-50964862;