rs1554643142

chr8-143818041-GGCTGGGCCTGCCCTATGTT-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.30

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]

ACMG classification

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	UniProt
PUF60	NM_078480.3	c.619_637del	p.Asn207ProfsTer3	frameshift_variant	8/12	ENST00000526683.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PUF60	ENST00000526683.6	c.619_637del	p.Asn207ProfsTer3	frameshift_variant	8/12	1	NM_078480.3

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

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 24, 2018	The c.619_637del19 variant in the PUF60 gene has been reported previously as a de novo variant with confirmed parentage in a patient with intellectual disability, developmental delay, microcephaly, horseshoe kidney, truncus arteriosus, submucous cleft palate and dysmorphic features (Low et al., 2017). This variant is not observed in large population cohorts (Lek et al., 2016). The c.619_637del19 variant causes a frameshift starting with codon Asparagine 207, changes this amino acid to a Proline residue, and creates a premature Stop codon at position 3 of the new reading frame, denoted p.Asn207ProfsX3. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. We interpret c.619_637del19 as a pathogenic variant. -
Likely pathogenic, criteria provided, single submitter	research	Bristol Genetics Laboratory, North Bristol NHS Trust	Jan 19, 2017	- -

8q24.3 microdeletion syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Jun 01, 2016

This variant was identified as de novo (maternity and paternity confirmed). -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554643142; hg19: chr8-144900211;