chr8-143829279-C-T

Variant names:

• chr8-143829279-C-T
• rs1064795388
• NM_078480.3:c.24+1G>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_078480.3(PUF60):​c.24+1G>A variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PUF60 NM_078480.3 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 3.00
• 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

ENSG00000305737 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.021428572 fraction of the gene.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-143829279-C-T is Pathogenic according to our data. Variant chr8-143829279-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 421831.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.24+1G>A		splice_donor intron	N/A	NP_510965.1
	PUF60	NM_001271098.2		c.24+1G>A		splice_donor intron	N/A	NP_001258027.1
	PUF60	NM_014281.5		c.24+1G>A		splice_donor intron	N/A	NP_055096.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PUF60	ENST00000526683.6	TSL:1 MANE Select	c.24+1G>A		splice_donor intron	N/A	ENSP00000434359.1
	PUF60	ENST00000349157.10	TSL:1	c.24+1G>A		splice_donor intron	N/A	ENSP00000322036.7
	ENSG00000305737	ENST00000812694.1		n.159C>T		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1113780 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 531718

African (AFR) AF: 0.00 AC: 0 AN: 23448

American (AMR) AF: 0.00 AC: 0 AN: 11550

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16170

East Asian (EAS) AF: 0.00 AC: 0 AN: 26618

South Asian (SAS) AF: 0.00 AC: 0 AN: 30856

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 24546

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4594

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 931100

Other (OTH) AF: 0.00 AC: 0 AN: 44898

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Feb 12, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28327570)

Jan 19, 2017

Bristol Genetics Laboratory, North Bristol NHS Trust

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	36
DANN	Uncertain	0.99
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Benign	0.16	N
PhyloP100		3.0
GERP RS		4.7
PromoterAI		-0.69	Under-expression
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.86		Position offset: -3
DS_DL_spliceai		0.99		Position offset: 1

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

Other links and lift over

dbSNP: rs1064795388; hg19: chr8-144911449;