8-143816620-T-TTATGAGTC

Variant names:

• chr8-143816620-T-TTATGAGTC
• NM_078480.3:c.1572_1579dupGACTCATA

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_078480.3(PUF60):​c.1572_1579dupGACTCATA​(p.Lys527ArgfsTer76) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PUF60 NM_078480.3 frameshift
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.55
• 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: Likely_pathogenic. The variant received 7 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 4 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-143816620-T-TTATGAGTC is Pathogenic according to our data. Variant chr8-143816620-T-TTATGAGTC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3346606.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PUF60	NM_078480.3	c.1572_1579dupGACTCATA	p.Lys527ArgfsTer76	frameshift_variant	Exon 12 of 12	ENST00000526683.6	NP_510965.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PUF60	ENST00000526683.6	c.1572_1579dupGACTCATA	p.Lys527ArgfsTer76	frameshift_variant	Exon 12 of 12	1	NM_078480.3	ENSP00000434359.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

PUF60-related disorder Pathogenic:1

Jun 06, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PUF60 c.1572_1579dup8 variant is predicted to result in a frameshift and premature protein termination (p.Lys527Argfs*76). To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. This variant is located in the terminal exon and multiple de novo frameshift variants in the terminal exon have been documented to be disease-causing (see for example, c.1577_1587del in Low et al. 2017. PubMed ID: 28327570; c.1673_1674del in Yamada et al. 2020. PubMed ID: 32851780). Frameshift variants in PUF60 are expected to be pathogenic. This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.6

Splicing

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

Other links and lift over

hg19: chr8-144898790;