rs1131692232

chr8-143818425-CCAAAGGGGG-C

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM4 PP3 PP5_Very_Strong

The NM_078480.3(PUF60):c.449_457del(p.Ala150_Phe152del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PUF60 NM_078480.3 inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 9.15

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 13 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_078480.3
• PM4: Nonframeshift variant in NON repetitive region in NM_078480.3.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 8-143818425-CCAAAGGGGG-C is Pathogenic according to our data. Variant chr8-143818425-CCAAAGGGGG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 430808.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143818425-CCAAAGGGGG-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PUF60	NM_078480.3	c.449_457del	p.Ala150_Phe152del	inframe_deletion	6/12	ENST00000526683.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PUF60	ENST00000526683.6	c.449_457del	p.Ala150_Phe152del	inframe_deletion	6/12	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:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

8q24.3 microdeletion syndrome Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	Jan 01, 2019	- -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Jun 07, 2017	- -
Likely pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	May 17, 2023	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 15, 2023	Not observed in large population cohorts (gnomAD); In-frame deletion of 3 amino acids in a non-repeat region; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 27535533, 36134573, 37303278) -
Likely pathogenic, no assertion criteria provided	clinical testing	Molecular Genetics laboratory, Necker Hospital	Jul 09, 2018	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 16, 2024

The c.449_457delCCCCCTTTG (p.A150_F152delL) alteration, located in coding exon 6 of the PUF60 gene, results from an in-frame deletion of 9 nucleotides at positions c.449 to c.457. This results in the deletion of 3 amino acids between codons 150 and 152. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been determined to be the result of a de novo mutation in multiple individuals with features consistent with Verheij syndrome (Brea-Fernández, 2022; Grimes, 2023; Ambry internal data). Additionally, this variant has been detected in one individual with developmental delay and intellectual disability, feeding difficulties, narrow palpebral fissures, prominent forehead, wide nasal bridge, joint laxity, and polydactyly (Fennell, 2022). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis (Choi, 2012). Based on the available evidence, this alteration is classified as pathogenic. -

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: rs1131692232; hg19: chr8-144900595;