chr8-143816630-C-G

Position:

chr8-143816630-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2

The NM_078480.3(PUF60):c.1570G>C(p.Glu524Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000186 in 1,613,760 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

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

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PUF60
NM_078480.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.15

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 Uncertain_significance. Variant got 3 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PUF60	NM_078480.3 link	c.1570G>C	p.Glu524Gln	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.1570G>C	p.Glu524Gln	missense_variant	12/12	1	NM_078480.3	ENSP00000434359.1		Q9UHX1-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000401

AC:

AN:

249144

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135198

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000464

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461534

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727032

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000376

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152226

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 17, 2024

The c.1570G>C (p.E524Q) alteration is located in exon 12 (coding exon 12) of the PUF60 gene. This alteration results from a G to C substitution at nucleotide position 1570, causing the glutamic acid (E) at amino acid position 524 to be replaced by a glutamine (Q). Based on data from gnomAD, the C allele has an overall frequency of <0.001% (1/249144) total alleles studied. The highest observed frequency was 0.005% (1/21546) of European (Finnish) alleles. This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). This alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

PUF60-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 14, 2023

The PUF60 c.1570G>C variant is predicted to result in the amino acid substitution p.Glu524Gln. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0046% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/8-144898800-C-G). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.46

BayesDel_addAF

Uncertain

0.019

BayesDel_noAF

Benign

-0.21

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.097

T;.;.;.;.;.

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.96

D;D;D;D;D;D

M_CAP

Benign

0.040

MetaRNN

Uncertain

0.72

D;D;D;D;D;D

MetaSVM

Benign

-1.2

MutationAssessor

Benign

1.6

L;.;.;.;.;.

PrimateAI

Pathogenic

0.79

PROVEAN

Benign

-2.0

N;N;N;N;N;N

REVEL

Benign

0.23

Sift

Benign

0.11

T;T;T;T;T;T

Sift4G

Benign

0.22

T;T;T;T;T;T

Polyphen

1.0

D;.;.;.;D;.

Vest4

0.78

MutPred

0.39

Gain of MoRF binding (P = 0.0446);.;.;.;.;.;

MVP

0.59

MPC

1.1

ClinPred

0.72

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.85

gMVP

0.93

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