NM_001953.5:c.972C>T

Variant names:

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

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.972C>T	p.Ala324Ala	synonymous	Exon 8 of 10	NP_001944.1	E5KRG5
	TYMP	NM_001257989.1		c.972C>T	p.Ala324Ala	synonymous	Exon 8 of 10	NP_001244918.1	P19971-2
	TYMP	NM_001113755.3		c.972C>T	p.Ala324Ala	synonymous	Exon 8 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.972C>T	p.Ala324Ala	synonymous	Exon 8 of 10	ENSP00000252029.3	P19971-1
	TYMP	ENST00000395681.6	TSL:1	c.972C>T	p.Ala324Ala	synonymous	Exon 8 of 10	ENSP00000379038.1	P19971-2
	TYMP	ENST00000395678.7	TSL:1	c.972C>T	p.Ala324Ala	synonymous	Exon 8 of 10	ENSP00000379036.3	P19971-1

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	not provided (4)
-	-	2	Mitochondrial DNA depletion syndrome 1 (2)
-	-	1	Fatal Infantile Cardioencephalomyopathy (1)
-	-	1	Mitochondrial complex IV deficiency, nuclear type 1 (1)
-	-	1	Spinal muscular atrophy (1)

Computational scores

Source: dbNSFP v4.9

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;