rs1085307135

Variant names:

• chr8-143818255-C-T
• rs1085307135
• NM_078480.3:c.541G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP2 PP3_Moderate PP5

The NM_078480.3(PUF60):​c.541G>A​(p.Glu181Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PUF60 NM_078480.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 7.79

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the PUF60 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 16 curated pathogenic missense variants (we use a threshold of 10). The gene has 6 curated benign missense variants. Gene score misZ: 4.4358 (above the threshold of 3.09). Trascript score misZ: 4.9183 (above the threshold of 3.09). GenCC associations: The gene is linked to 8q24.3 microdeletion syndrome, syndromic intellectual disability.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.863
• PP5: Variant 8-143818255-C-T is Pathogenic according to our data. Variant chr8-143818255-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 425567.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PUF60	NM_078480.3	c.541G>A	p.Glu181Lys	missense_variant	Exon 7 of 12	ENST00000526683.6	NP_510965.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PUF60	ENST00000526683.6	c.541G>A	p.Glu181Lys	missense_variant	Exon 7 of 12	1	NM_078480.3	ENSP00000434359.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2

Jan 03, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate reduced PUF60 protein abundance and activity (Krlovicov et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28135719, 31785789, 28074499, 28327570, 29788428, 28471317) -

Jan 19, 2017

Bristol Genetics Laboratory, North Bristol NHS Trust

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

8q24.3 microdeletion syndrome Pathogenic:1

Dec 21, 2018

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Inborn genetic diseases Uncertain:1

Sep 16, 2016

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.25	T;.;.;.;.;.;.;T;.;T
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.86	D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.21	D
MutationAssessor	Uncertain	2.3	M;.;.;.;.;.;.;.;.;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.7	D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.66
Sift	Benign	0.030	D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.032	D;D;D;D;D;D;.;T;.;.
Polyphen		1.0	D;.;.;D;D;.;.;.;.;.
Vest4		0.75
MutPred		0.71		Gain of ubiquitination at E181 (P = 0.0192);.;.;.;.;.;.;.;.;.;
MVP		0.69
MPC		3.4
ClinPred		0.98	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.82
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1085307135; hg19: chr8-144900425;