Variant 8-143816785-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP2PP3

The NM_078480.3(PUF60):c.1415C>G(p.Pro472Arg) 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

PUF60
NM_078480.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.94

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PUF60. . Gene score misZ: 4.4358 (greater than the threshold 3.09). Trascript score misZ: 4.9183 (greater than threshold 3.09). The gene has 16 curated pathogenic missense variants (we use a threshold of 10). The gene has 6 curated benign missense variants. GenCC has associacion of the gene with 8q24.3 microdeletion syndrome, syndromic intellectual disability.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.773

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PUF60	NM_078480.3 link	c.1415C>G	p.Pro472Arg	missense_variant	12/12	ENST00000526683.6	NP_510965.1	Q9UHX1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PUF60	ENST00000526683.6 link	c.1415C>G	p.Pro472Arg	missense_variant	12/12	1	NM_078480.3	ENSP00000434359.1		Q9UHX1-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jul 05, 2024

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.83

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.020

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.36

T;.;.;.;.;.

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

D;D;D;D;D;D

M_CAP

Benign

0.083

MetaRNN

Pathogenic

0.77

D;D;D;D;D;D

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.2

M;.;.;.;.;.

PrimateAI

Pathogenic

0.88

PROVEAN

Uncertain

-3.8

D;D;D;D;D;D

REVEL

Uncertain

0.51

Sift

Uncertain

0.021

D;D;D;D;D;D

Sift4G

Uncertain

0.040

D;T;T;T;D;T

Polyphen

1.0

D;.;.;.;D;.

Vest4

0.87

MutPred

0.42

Gain of MoRF binding (P = 0.0369);.;.;.;.;.;

MVP

0.58

MPC

1.1

ClinPred

0.97

GERP RS

5.4

RBP_binding_hub_radar

1.1

RBP_regulation_power_radar

2.8

Varity_R

0.75

gMVP

0.97

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over