rs1554643142

Variant names:

• chr8-143818041-GGCTGGGCCTGCCCTATGTT-G
• rs1554643142
• NM_078480.3:c.619_637delAACATAGGGCAGGCCCAGC

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_078480.3(PUF60):​c.619_637delAACATAGGGCAGGCCCAGC​(p.Asn207ProfsTer3) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. 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:4
• Conservation: PhyloP100: 9.30
• Publications: 0 publications found

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]

PUF60 Gene-Disease associations (from GenCC):

• 8q24.3 microdeletion syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
• syndromic intellectual disability

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 8-143818041-GGCTGGGCCTGCCCTATGTT-G is Pathogenic according to our data. Variant chr8-143818041-GGCTGGGCCTGCCCTATGTT-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 425573.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_078480.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PUF60	NM_078480.3	MANE Select	c.619_637delAACATAGGGCAGGCCCAGC	p.Asn207ProfsTer3	frameshift	Exon 8 of 12	NP_510965.1
	PUF60	NM_001362895.2		c.730_748delAACATAGGGCAGGCCCAGC	p.Asn244ProfsTer3	frameshift	Exon 9 of 13	NP_001349824.1
	PUF60	NM_001362896.2		c.730_748delAACATAGGGCAGGCCCAGC	p.Asn244ProfsTer3	frameshift	Exon 9 of 13	NP_001349825.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PUF60	ENST00000526683.6	TSL:1 MANE Select	c.619_637delAACATAGGGCAGGCCCAGC	p.Asn207ProfsTer3	frameshift	Exon 8 of 12	ENSP00000434359.1
	PUF60	ENST00000349157.10	TSL:1	c.568_586delAACATAGGGCAGGCCCAGC	p.Asn190ProfsTer3	frameshift	Exon 7 of 11	ENSP00000322036.7
	PUF60	ENST00000453551.6	TSL:1	c.490_508delAACATAGGGCAGGCCCAGC	p.Asn164ProfsTer3	frameshift	Exon 8 of 12	ENSP00000402953.2

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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Apr 05, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift 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)

Jan 19, 2017

Bristol Genetics Laboratory, North Bristol NHS Trust

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

8q24.3 microdeletion syndrome Pathogenic:1

Jun 01, 2016

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.3
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs1554643142; hg19: chr8-144900211;