rs1064792855

Variant names:

• chr22-50527283-G-A
• rs1064792855
• NM_001953.5:c.647C>T

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1 PM2 PP3 PP5_Very_Strong

The NM_001953.5(TYMP):​c.647C>T​(p.Ala216Val) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000549 in 1,457,710 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. A216A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: TYMP NM_001953.5 missense, splice_region
• Scores: Splicing: ADA: 0.9882
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 4.69
• 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]

TYMP Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• mitochondrial DNA depletion syndrome 1

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• mitochondrial neurogastrointestinal encephalomyopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_001953.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 22-50527283-G-A is Pathogenic according to our data. Variant chr22-50527283-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 223004.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TYMP	NM_001953.5	MANE Select	c.647C>T	p.Ala216Val	missense splice_region	Exon 6 of 10	NP_001944.1
	TYMP	NM_001257989.1		c.647C>T	p.Ala216Val	missense splice_region	Exon 6 of 10	NP_001244918.1
	TYMP	NM_001113755.3		c.647C>T	p.Ala216Val	missense splice_region	Exon 6 of 10	NP_001107227.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TYMP	ENST00000252029.8	TSL:1 MANE Select	c.647C>T	p.Ala216Val	missense splice_region	Exon 6 of 10	ENSP00000252029.3
	TYMP	ENST00000395681.6	TSL:1	c.647C>T	p.Ala216Val	missense splice_region	Exon 6 of 10	ENSP00000379038.1
	TYMP	ENST00000395678.7	TSL:1	c.647C>T	p.Ala216Val	missense splice_region	Exon 6 of 10	ENSP00000379036.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000798 AC: 2 AN: 250470 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000549 AC: 8 AN: 1457710 Hom.: 0 Cov.: 31 AF XY: 0.00000827 AC XY: 6 AN XY: 725466

African (AFR) AF: 0.00 AC: 0 AN: 33420

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 86188

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52958

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00000722 AC: 8 AN: 1108636

Other (OTH) AF: 0.00 AC: 0 AN: 60238

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000468 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Mitochondrial DNA depletion syndrome 1 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.89	D
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		4.7
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-3.2	D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.011	D
Polyphen		1.0	D
Vest4		0.49
MutPred		0.87		Gain of sheet (P = 0.0827)
MVP		0.89
MPC		1.3
ClinPred		0.94	D
GERP RS		4.7
PromoterAI		-0.025	Neutral
Varity_R		0.78
gMVP		0.91
Mutation Taster		=2/98	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.89
SpliceAI score (max)		0.11		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: rs1064792855; hg19: chr22-50965712;