22-50529755-C-T

Variant names:

• chr22-50529755-C-T
• rs202144233
• ENST00000487577.5:c.-46G>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_001257988.1(TYMP):​c.-45-1G>A variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000071 in 1,407,910 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: TYMP NM_001257988.1 splice_acceptor, intron
• Scores: Splicing: ADA: 0.00003153
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.806
• 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]

CIMAP1B (HGNC:34388): (ciliary microtubule associated protein 1B) Predicted to be active in cytoskeleton. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 5.6, offset of 35, new splice context is: cgtgtcaggcatccccgcAGgcc. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001257988.1. 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.-10-36G>A		intron	N/A	NP_001944.1	E5KRG5
	TYMP	NM_001113756.3		c.-46G>A		5_prime_UTR	Exon 1 of 9	NP_001107228.1	E5KRG5
	TYMP	NM_001257989.1		c.-10-36G>A		intron	N/A	NP_001244918.1	P19971-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TYMP	ENST00000487577.5	TSL:1	c.-46G>A		5_prime_UTR	Exon 1 of 9	ENSP00000498844.1	P19971-1
	TYMP	ENST00000252029.8	TSL:1 MANE Select	c.-10-36G>A		intron	N/A	ENSP00000252029.3	P19971-1
	TYMP	ENST00000395681.6	TSL:1	c.-10-36G>A		intron	N/A	ENSP00000379038.1	P19971-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000540 AC: 1 AN: 185318 AF XY: 0.00000983

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.10e-7 AC: 1 AN: 1407910 Hom.: 0 Cov.: 28 AF XY: 0.00000144 AC XY: 1 AN XY: 696096

African (AFR) AF: 0.00 AC: 0 AN: 32348

American (AMR) AF: 0.00 AC: 0 AN: 38688

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25008

East Asian (EAS) AF: 0.00 AC: 0 AN: 37880

South Asian (SAS) AF: 0.0000123 AC: 1 AN: 81608

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48922

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4338

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1081074

Other (OTH) AF: 0.00 AC: 0 AN: 58044

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	3.6
DANN	Benign	0.83
PhyloP100		-0.81
PromoterAI		-0.074	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000032
dbscSNV1_RF	Benign	0.0
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: rs202144233; hg19: chr22-50968184;