rs1064792865

Positions:

• chr22-50527716-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_001953.5(TYMP):​c.518T>G​(p.Met173Arg) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M173I) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TYMP NM_001953.5 missense, splice_region
• Scores: Splicing: ADA: 0.2385
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 4.25

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984
• PP5: Variant 22-50527716-A-C is Pathogenic according to our data. Variant chr22-50527716-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 223031.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TYMP	NM_001953.5	c.518T>G	p.Met173Arg	missense_variant, splice_region_variant	5/10	ENST00000252029.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TYMP	ENST00000252029.8	c.518T>G	p.Met173Arg	missense_variant, splice_region_variant	5/10	1	NM_001953.5	P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Mitochondrial DNA depletion syndrome 1 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	GeneReviews	Jan 14, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 21, 2024	Variant summary: TYMP c.518T>G (p.Met173Arg) results in a non-conservative amino acid change located in the Glycosyl transferase, family 3 domain (IPR000312) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. This variant alters the nucleotide within the exonic splice region in exon 5. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251330 control chromosomes. c.518T>G has been reported in the literature at a homozygous state in three Dominican individuals affected with Mitochondrial DNA Depletion Syndrome 1 (MNGIE type) (example, Garone_2011, Hirano_2004, Nishino_2000). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 21933806, 14720311, 10852545). ClinVar contains an entry for this variant (Variation ID: 223031). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Congenital adrenal hyperplasia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 21, 2024

Variant summary: HSD3B2 c.518T>G (p.Leu173Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251192 control chromosomes. c.518T>G has been reported in the literature in individuals affected with Congenital Adrenal Hyperplasia. These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Uncertain	23
DANN	Uncertain	0.97
DEOGEN2	Pathogenic	0.96	D;.;D;D;D
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Uncertain	0.90	D
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.9	M;M;M;M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-4.6	D;D;D;D;D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0040	D;D;D;D;D
Sift4G	Benign	0.094	T;T;T;T;D
Polyphen		0.99	D;.;D;D;.
Vest4		0.83
MutPred		0.88		Gain of catalytic residue at M173 (P = 0.0331);Gain of catalytic residue at M173 (P = 0.0331);Gain of catalytic residue at M173 (P = 0.0331);Gain of catalytic residue at M173 (P = 0.0331);.;
MVP		0.86
MPC		1.5
ClinPred		1.0	D
GERP RS		4.0
Varity_R		0.98
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.24
dbscSNV1_RF	Benign	0.29
SpliceAI score (max)		0.36		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.36		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs1064792865; hg19: chr22-50966145;