rs1554643142

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_078480.3(PUF60):​c.619_637del​(p.Asn207ProfsTer3) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Consequence

PUF60
NM_078480.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 9.30
Variant links:
Genes affected
PUF60 (HGNC:17042): (poly(U) binding splicing factor 60) This gene encodes a nucleic acid-binding protein that plays a role in a variety of nuclear processes, including pre-mRNA splicing and transcriptional regulation. The encoded protein forms a complex with the far upstream DNA element (FUSE) and FUSE-binding protein at the myelocytomatosis oncogene (MYC) promoter. This complex represses MYC transcription through the core-TFIIH basal transcription factor. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Aug 2012]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 8-143818041-GGCTGGGCCTGCCCTATGTT-G is Pathogenic according to our data. Variant chr8-143818041-GGCTGGGCCTGCCCTATGTT-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 425573.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143818041-GGCTGGGCCTGCCCTATGTT-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PUF60NM_078480.3 linkuse as main transcriptc.619_637del p.Asn207ProfsTer3 frameshift_variant 8/12 ENST00000526683.6 NP_510965.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PUF60ENST00000526683.6 linkuse as main transcriptc.619_637del p.Asn207ProfsTer3 frameshift_variant 8/121 NM_078480.3 ENSP00000434359 Q9UHX1-1

Frequencies

GnomAD3 genomes
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitterresearchBristol Genetics Laboratory, North Bristol NHS TrustJan 19, 2017- -
Pathogenic, criteria provided, single submitterclinical testingGeneDxApr 05, 2024Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28327570, 27535533) -
8q24.3 microdeletion syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics, University of Leipzig Medical CenterJun 01, 2016This variant was identified as de novo (maternity and paternity confirmed). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

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: rs1554643142; hg19: chr8-144900211; API