chr22-50527716-A-G

Variant names:

• chr22-50527716-A-G
• rs1064792865
• NM_001953.5:c.518T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_001953.5(TYMP):​c.518T>C​(p.Met173Thr) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000137 in 1,461,176 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 predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M173R) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TYMP NM_001953.5 missense, splice_region
• Scores: Splicing: ADA: 0.08306
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.25
• Publications: 0 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: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr22-50527716-A-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 223031.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.942

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.518T>C	p.Met173Thr	missense splice_region	Exon 5 of 10	NP_001944.1
	TYMP	NM_001257989.1		c.518T>C	p.Met173Thr	missense splice_region	Exon 5 of 10	NP_001244918.1
	TYMP	NM_001113755.3		c.518T>C	p.Met173Thr	missense splice_region	Exon 5 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.518T>C	p.Met173Thr	missense splice_region	Exon 5 of 10	ENSP00000252029.3
	TYMP	ENST00000395681.6	TSL:1	c.518T>C	p.Met173Thr	missense splice_region	Exon 5 of 10	ENSP00000379038.1
	TYMP	ENST00000395678.7	TSL:1	c.518T>C	p.Met173Thr	missense splice_region	Exon 5 of 10	ENSP00000379036.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461176 Hom.: 0 Cov.: 35 AF XY: 0.00000275 AC XY: 2 AN XY: 726892

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53090

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111742

Other (OTH) AF: 0.00 AC: 0 AN: 60362

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.88	D
Eigen	Uncertain	0.28
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.52	T
M_CAP	Pathogenic	0.43	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		4.3
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-4.2	D
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.054	T
Polyphen		0.93	P
Vest4		0.55
MutPred		0.77		Gain of disorder (P = 0.1608)
MVP		0.84
MPC		1.2
ClinPred		0.99	D
GERP RS		4.0
PromoterAI		0.038	Neutral
Varity_R		0.88
gMVP		0.77
Mutation Taster		=7/93	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.083
dbscSNV1_RF	Benign	0.15
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.23		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1064792865; hg19: chr22-50966145;