chr22-50525807-G-A

Variant names:

• chr22-50525807-G-A
• rs11479
• NM_001953.5:c.1412C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001953.5(TYMP):​c.1412C>T​(p.Ser471Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0995 in 1,610,390 control chromosomes in the GnomAD database, including 9,556 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S471S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.090 (778 hom., cov: 35)
  • Exomes 𝑓: 0.10 (8778 hom.)
• Consequence: TYMP NM_001953.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 1.14
• Publications: 52 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0021177828).
• BP6: Variant 22-50525807-G-A is Benign according to our data. Variant chr22-50525807-G-A is described in ClinVar as Benign. ClinVar VariationId is 130693.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.241 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.1412C>T	p.Ser471Leu	missense	Exon 10 of 10	NP_001944.1	E5KRG5
	TYMP	NM_001257989.1		c.1427C>T	p.Ser476Leu	missense	Exon 10 of 10	NP_001244918.1	P19971-2
	TYMP	NM_001113755.3		c.1412C>T	p.Ser471Leu	missense	Exon 10 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.1412C>T	p.Ser471Leu	missense	Exon 10 of 10	ENSP00000252029.3	P19971-1
	TYMP	ENST00000395681.6	TSL:1	c.1427C>T	p.Ser476Leu	missense	Exon 10 of 10	ENSP00000379038.1	P19971-2
	TYMP	ENST00000395678.7	TSL:1	c.1412C>T	p.Ser471Leu	missense	Exon 10 of 10	ENSP00000379036.3	P19971-1

Frequencies

GnomAD3 genomes AF: 0.0899 AC: 13689 AN: 152208 Hom.: 778 Cov.: 35

Gnomad AFR AF: 0.0507

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.133

Gnomad ASJ AF: 0.0697

Gnomad EAS AF: 0.253

Gnomad SAS AF: 0.191

Gnomad FIN AF: 0.0908

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0866

Gnomad OTH AF: 0.0969

GnomAD2 exomes AF: 0.128 AC: 29384 AN: 230034 AF XY: 0.125

Gnomad AFR exome AF: 0.0493

Gnomad AMR exome AF: 0.207

Gnomad ASJ exome AF: 0.0688

Gnomad EAS exome AF: 0.258

Gnomad FIN exome AF: 0.0933

Gnomad NFE exome AF: 0.0885

Gnomad OTH exome AF: 0.103

GnomAD4 exome AF: 0.100 AC: 146515 AN: 1458068 Hom.: 8778 Cov.: 39 AF XY: 0.102 AC XY: 74188 AN XY: 725332

African (AFR) AF: 0.0482 AC: 1609 AN: 33392

American (AMR) AF: 0.195 AC: 8676 AN: 44494

Ashkenazi Jewish (ASJ) AF: 0.0685 AC: 1785 AN: 26060

East Asian (EAS) AF: 0.240 AC: 9502 AN: 39612

South Asian (SAS) AF: 0.172 AC: 14851 AN: 86168

European-Finnish (FIN) AF: 0.0947 AC: 4889 AN: 51608

Middle Eastern (MID) AF: 0.0638 AC: 365 AN: 5722

European-Non Finnish (NFE) AF: 0.0885 AC: 98278 AN: 1110890

Other (OTH) AF: 0.109 AC: 6560 AN: 60122

GnomAD4 genome AF: 0.0899 AC: 13695 AN: 152322 Hom.: 778 Cov.: 35 AF XY: 0.0928 AC XY: 6912 AN XY: 74480

African (AFR) AF: 0.0506 AC: 2103 AN: 41586

American (AMR) AF: 0.133 AC: 2037 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0697 AC: 242 AN: 3470

East Asian (EAS) AF: 0.253 AC: 1310 AN: 5186

South Asian (SAS) AF: 0.191 AC: 925 AN: 4832

European-Finnish (FIN) AF: 0.0908 AC: 964 AN: 10618

Middle Eastern (MID) AF: 0.0171 AC: 5 AN: 292

European-Non Finnish (NFE) AF: 0.0866 AC: 5889 AN: 68004

Other (OTH) AF: 0.0969 AC: 205 AN: 2116

Alfa AF: 0.0890 Hom.: 849

Bravo AF: 0.0900

TwinsUK AF: 0.0823 AC: 305

ALSPAC AF: 0.0924 AC: 356

ESP6500AA AF: 0.0440 AC: 183

ESP6500EA AF: 0.0807 AC: 663

ExAC AF: 0.120 AC: 14146

Asia WGS AF: 0.229 AC: 793 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	4	not specified (4)
-	-	3	Mitochondrial DNA depletion syndrome 1 (3)
-	-	1	Fatal Infantile Cardioencephalomyopathy (1)
-	-	1	Spinal muscular atrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.13
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.72
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.67	T
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	1.7	L
PhyloP100		1.1
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.61	N
REVEL	Uncertain	0.32
Sift	Benign	0.40	T
Sift4G	Benign	0.33	T
Polyphen		0.99	D
Vest4		0.28
MPC		0.92
ClinPred		0.033	T
GERP RS		2.2
PromoterAI		0.049	Neutral
Varity_R		0.14
gMVP		0.56
Mutation Taster		=86/14	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs11479; hg19: chr22-50964236; COSMIC: COSV52688025; COSMIC: COSV52688025;