22-50526673-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001953.5(TYMP):c.831G>A(p.Leu277=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00644 in 1,551,898 control chromosomes in the GnomAD database, including 453 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L277L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.032 (235 hom., cov: 33)
  • Exomes 𝑓: 0.0037 (218 hom.)
• Consequence: TYMP NM_001953.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.729

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 Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 22-50526673-C-T is Benign according to our data. Variant chr22-50526673-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 137873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.729 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.106 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TYMP	NM_001953.5	c.831G>A	p.Leu277=	synonymous_variant	7/10	ENST00000252029.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TYMP	ENST00000252029.8	c.831G>A	p.Leu277=	synonymous_variant	7/10	1	NM_001953.5	P2

Frequencies

GnomAD3 genomes AF: 0.0320 AC: 4866 AN: 152230 Hom.: 233 Cov.: 33

Gnomad AFR AF: 0.108

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0165

Gnomad ASJ AF: 0.00662

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.000603

Gnomad OTH AF: 0.0225

GnomAD3 exomes AF: 0.00832 AC: 1221 AN: 146814 Hom.: 57 AF XY: 0.00647 AC XY: 517 AN XY: 79894

Gnomad AFR exome AF: 0.116

Gnomad AMR exome AF: 0.00631

Gnomad ASJ exome AF: 0.00946

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000173

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000745

Gnomad OTH exome AF: 0.00640

GnomAD4 exome AF: 0.00366 AC: 5117 AN: 1399550 Hom.: 218 Cov.: 36 AF XY: 0.00324 AC XY: 2242 AN XY: 691454

Gnomad4 AFR exome AF: 0.110

Gnomad4 AMR exome AF: 0.00812

Gnomad4 ASJ exome AF: 0.00825

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000200

Gnomad4 FIN exome AF: 0.0000238

Gnomad4 NFE exome AF: 0.000464

Gnomad4 OTH exome AF: 0.00918

GnomAD4 genome AF: 0.0320 AC: 4872 AN: 152348 Hom.: 235 Cov.: 33 AF XY: 0.0314 AC XY: 2336 AN XY: 74504

Gnomad4 AFR AF: 0.108

Gnomad4 AMR AF: 0.0165

Gnomad4 ASJ AF: 0.00662

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000603

Gnomad4 OTH AF: 0.0223

Alfa AF: 0.0200 Hom.: 22

Bravo AF: 0.0365

Asia WGS AF: 0.00808 AC: 28 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 30, 2019	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 29, 2016	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 18, 2011	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Mitochondrial neurogastrointestinal encephalomyopathy Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Mitochondrial complex IV deficiency, nuclear type 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Mitochondrial DNA depletion syndrome 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Fatal Infantile Cardioencephalomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
Cadd	Benign	15
Dann	Benign	0.93

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs8141558; hg19: chr22-50965102;