Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2PP5_ModerateBP4

The NM_078480.3(PUF60):c.475G>A(p.Asp159Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Consequence

PUF60
NM_078480.3 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 6.04

Publications

5 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 8-143818408-C-T is Pathogenic according to our data. Variant chr8-143818408-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 425569.Status of the report is criteria_provided_single_submitter, 1 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.27469605). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_078480.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PUF60	NM_078480.3	MANE Select	c.475G>A	p.Asp159Asn	missense	Exon 6 of 12	NP_510965.1
PUF60	NM_001362895.2		c.586G>A	p.Asp196Asn	missense	Exon 7 of 13	NP_001349824.1
PUF60	NM_001362896.2		c.586G>A	p.Asp196Asn	missense	Exon 7 of 13	NP_001349825.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PUF60	ENST00000526683.6	TSL:1 MANE Select	c.475G>A	p.Asp159Asn	missense	Exon 6 of 12	ENSP00000434359.1
PUF60	ENST00000349157.10	TSL:1	c.424G>A	p.Asp142Asn	missense	Exon 5 of 11	ENSP00000322036.7
PUF60	ENST00000453551.6	TSL:1	c.346G>A	p.Asp116Asn	missense	Exon 6 of 12	ENSP00000402953.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions as Germline

Significance:Likely pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.54

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.051

Eigen

Benign

-0.096

Eigen_PC

Benign

0.11

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

M_CAP

Benign

0.034

MetaRNN

Benign

0.27

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.2

PhyloP100

6.0

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

1.5

REVEL

Benign

0.14

Sift

Benign

0.92

Sift4G

Benign

1.0

Polyphen

0.060

Vest4

0.73

MutPred

0.45

Gain of MoRF binding (P = 0.059)

MVP

0.34

MPC

1.7

ClinPred

0.89

GERP RS

5.2

PromoterAI

-0.029

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.1

Varity_R

0.83

gMVP

0.90

Mutation Taster

=4/96

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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rs1085307137

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over