8-143818494-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2PM5PP3_ModeratePP5_Very_Strong

The NM_078480.3(PUF60):c.389G>A(p.Arg130His) 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. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R130C) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PUF60
NM_078480.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 7.79

Publications

0 publications found

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 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

PUF60 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr8-143818495-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 3777301.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.866

PP5

Variant 8-143818494-C-T is Pathogenic according to our data. Variant chr8-143818494-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 488376.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PUF60	NM_078480.3 link	c.389G>A	p.Arg130His	missense_variant	Exon 6 of 12	ENST00000526683.6	NP_510965.1	Q9UHX1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PUF60	ENST00000526683.6 link	c.389G>A	p.Arg130His	missense_variant	Exon 6 of 12	1	NM_078480.3	ENSP00000434359.1		Q9UHX1-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1455154

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

723354

African (AFR)

AF:

0.00

AC:

AN:

33384

American (AMR)

AF:

0.00

AC:

AN:

44068

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25886

East Asian (EAS)

AF:

0.00

AC:

AN:

39498

South Asian (SAS)

AF:

0.00

AC:

AN:

85314

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51370

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1109780

Other (OTH)

AF:

0.00

AC:

AN:

60092

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

8q24.3 microdeletion syndrome

Pathogenic:2

Aug 17, 2020

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant has been previously reported as a de novo change in two patients with Verheij syndrome (VRJS, MIM: #615583) (PMID: 30160830, 29300383). It is absent from the gnomAD population database and thus is presumed to be rare. The c.389G>A (p.Arg130His) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.389G>A (p.Arg130His) variant is classified as Likely Pathogenic. -

Oct 27, 2017

Sbielas Lab-Department of Human Genetics University of Michigan, University of Michigan Medical School

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

CHARGE syndrome

Pathogenic:1

University of Washington Center for Mendelian Genomics, University of Washington

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

not provided

Pathogenic:1

Dec 23, 2021

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30160830, 29300383) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.32

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.44

T;.;.;.;.;.;.;T;.;T

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

D;D;D;D;D;D;D;D;D;D

M_CAP

Uncertain

0.23

MetaRNN

Pathogenic

0.87

D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.36

MutationAssessor

Uncertain

2.6

M;.;.;.;.;.;.;.;.;.

PhyloP100

7.8

PrimateAI

Pathogenic

0.92

PROVEAN

Uncertain

-4.3

D;D;D;D;D;D;D;D;D;D

REVEL

Pathogenic

0.71

Sift

Uncertain

0.0010

D;D;D;D;D;D;D;D;D;D

Sift4G

Benign

0.073

T;T;T;T;T;T;.;T;.;.

Polyphen

1.0

D;.;.;D;D;.;.;.;.;.

Vest4

0.56

MutPred

0.63

Loss of MoRF binding (P = 0.0067);.;.;.;.;.;.;.;.;.;

MVP

0.90

MPC

3.4

ClinPred

0.99

GERP RS

5.2

PromoterAI

-0.0055

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.76

gMVP

0.97

Mutation Taster

=1/99

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over