chr8-143816711-T-C

Position:

chr8-143816711-T-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2

The NM_078480.3(PUF60):c.1489A>G(p.Ile497Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000093 in 1,613,738 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

PUF60
NM_078480.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 7.25

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

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). GenCC has associacion of gene with 8q24.3 microdeletion syndrome, syndromic intellectual disability.

BP4

Computational evidence support a benign effect (MetaRNN=0.18256691).

BS2

High AC in GnomAdExome4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PUF60	NM_078480.3 linkuse as main transcript	c.1489A>G	p.Ile497Val	missense_variant	12/12	ENST00000526683.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PUF60	ENST00000526683.6 linkuse as main transcript	c.1489A>G	p.Ile497Val	missense_variant	12/12	1	NM_078480.3		Q9UHX1-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000958

AC:

AN:

1461530

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727028

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000809

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152208

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.00000826

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

8q24.3 microdeletion syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 06, 2020

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 18, 2021

The c.1489A>G (p.I497V) alteration is located in exon 12 (coding exon 12) of the PUF60 gene. This alteration results from a A to G substitution at nucleotide position 1489, causing the isoleucine (I) at amino acid position 497 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.59

CADD

Benign

DANN

Benign

0.90

DEOGEN2

Benign

0.064

T;.;.;.;.;.

Eigen

Benign

-0.26

Eigen_PC

Benign

0.015

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.91

D;D;D;D;D;D

M_CAP

Benign

0.016

MetaRNN

Benign

0.18

T;T;T;T;T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

-1.2

N;.;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-0.23

N;N;N;N;N;N

REVEL

Benign

0.14

Sift

Benign

0.74

T;T;T;T;T;T

Sift4G

Benign

0.91

T;T;T;T;T;T

Polyphen

0.0020

B;.;.;.;B;.

Vest4

0.60

MutPred

0.47

Gain of ubiquitination at K502 (P = 0.1489);.;.;.;.;.;

MVP

0.30

MPC

0.91

ClinPred

0.21

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.52

gMVP

0.65

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over