rs121917902

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_170753.3(PGBD3):​c.-48C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,461,566 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

PGBD3
NM_170753.3 5_prime_UTR_premature_start_codon_gain

Scores

4
2
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 3.08
Variant links:
Genes affected
ERCC6 (HGNC:3438): (ERCC excision repair 6, chromatin remodeling factor) This gene encodes a DNA-binding protein that is important in transcription-coupled excision repair. The encoded protein has ATP-stimulated ATPase activity, interacts with several transcription and excision repair proteins, and may promote complex formation at DNA repair sites. Mutations in this gene are associated with Cockayne syndrome type B and cerebrooculofacioskeletal syndrome 1. Alternative splicing occurs between a splice site from exon 5 of this gene to the 3' splice site upstream of the open reading frame (ORF) of the adjacent gene, piggyback-derived-3 (GeneID:267004), which activates the alternative polyadenylation site downstream of the piggyback-derived-3 ORF. The resulting transcripts encode a fusion protein that shares sequence with the product of each individual gene. [provided by RefSeq, Mar 2016]
PGBD3 (HGNC:19400): (piggyBac transposable element derived 3) This gene is a member of a small family of genes derived from piggyBac transposable elements. The encoded protein contains a zinc-ribbon domain characteristic of transposon-derived proteins and may function as a regulator of transcription. Alternative splicing occurs between a splice site from exon 5 of the adjacent upstream gene 'excision repair cross-complementation group 6' (ERCC6, GeneID: 2074) and the 3' splice site upstream of the open reading frame (ORF) of this gene, which activates the alternative polyadenylation site downstream of the piggyback-derived-3 ORF. The resulting transcripts encode a fusion protein that shares sequence with the product of each individual gene. Pseudogenes for this gene are defined on chromosomes 4, 5 and 12. [provided by RefSeq, Mar 2016]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
BayesDel_addAF computational evidence supports a deleterious effect, 0.625
PP5
Variant 10-49524073-G-A is Pathogenic according to our data. Variant chr10-49524073-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 1703.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ERCC6NM_000124.4 linkuse as main transcriptc.1357C>T p.Arg453* stop_gained 5/21 ENST00000355832.10 NP_000115.1 Q03468-1Q59FF6
ERCC6NM_001277058.2 linkuse as main transcriptc.1357C>T p.Arg453* stop_gained 5/6 ENST00000447839.7 NP_001263987.1 P0DP91-1A8K4Q3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ERCC6ENST00000355832.10 linkuse as main transcriptc.1357C>T p.Arg453* stop_gained 5/211 NM_000124.4 ENSP00000348089.5 Q03468-1
ERCC6ENST00000447839.7 linkuse as main transcriptc.1357C>T p.Arg453* stop_gained 5/62 NM_001277058.2 ENSP00000387966.2 P0DP91-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000753
AC:
11
AN:
1461566
Hom.:
0
Cov.:
31
AF XY:
0.00000963
AC XY:
7
AN XY:
727112
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000989
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Cockayne syndrome type 2 Pathogenic:3
Pathogenic, no assertion criteria providedliterature onlyOMIMMay 01, 1999- -
Pathogenic, criteria provided, single submitterclinical testingClaritas GenomicsJul 29, 2013- -
Pathogenic, criteria provided, single submitterresearchDepartment of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences-- -
Cerebrooculofacioskeletal syndrome 1;C0265201:DE SANCTIS-CACCHIONE SYNDROME;C0751038:Cockayne syndrome type 2 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingCounsylOct 12, 2017- -
Cerebrooculofacioskeletal syndrome 1;C0265201:DE SANCTIS-CACCHIONE SYNDROME;C0684249:Lung carcinoma;C0751038:Cockayne syndrome type 2;C3151063:Age related macular degeneration 5;C3551173:UV-sensitive syndrome 1;C4310783:Premature ovarian failure 11 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsOct 31, 2018- -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 21, 2024This sequence change creates a premature translational stop signal (p.Arg453*) in the ERCC6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ERCC6 are known to be pathogenic (PMID: 18628313, 29572252). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with Cockayne syndrome (PMID: 9443879, 29572252). ClinVar contains an entry for this variant (Variation ID: 1703). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.57
CADD
Pathogenic
37
DANN
Uncertain
1.0
Eigen
Pathogenic
0.94
Eigen_PC
Pathogenic
0.81
FATHMM_MKL
Uncertain
0.93
D
Vest4
0.81
GERP RS
6.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs121917902; hg19: chr10-50732119; API