chr8-143816741-A-G

Variant names:

• chr8-143816741-A-G
• rs2130205866
• NM_078480.3:c.1459T>C

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_078480.3(PUF60):​c.1459T>C​(p.Cys487Arg) 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. 14/22 in silico tools predict a damaging 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
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.38
• Publications: 0 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM1: In a domain RRM 3; atypical (size 87) in uniprot entity PUF60_HUMAN there are 7 pathogenic changes around while only 1 benign (88%) in NM_078480.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.968
• PP5: Variant 8-143816741-A-G is Pathogenic according to our data. Variant chr8-143816741-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1334132.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PUF60	NM_078480.3	c.1459T>C	p.Cys487Arg	missense_variant	Exon 12 of 12	ENST00000526683.6	NP_510965.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PUF60	ENST00000526683.6	c.1459T>C	p.Cys487Arg	missense_variant	Exon 12 of 12	1	NM_078480.3	ENSP00000434359.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

8q24.3 microdeletion syndrome Pathogenic:1

-

Randwick Genomics Laboratory, Prince of Wales Hospital Sydney, Australia, New South Wales Health Pathology

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS2_mod, PM2, PM1, PP2, PP3 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D;.;.;.;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D
MetaSVM	Benign	-0.56	T
MutationAssessor	Pathogenic	4.2	H;.;.;.;.;.
PhyloP100		8.4
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-11	D;D;D;D;D;D
REVEL	Pathogenic	0.67
Sift	Pathogenic	0.0	D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;D;.
Vest4		0.91
MutPred		0.86		Gain of disorder (P = 0.0108);.;.;.;.;.;
MVP		0.80
MPC		2.1
ClinPred		1.0	D
GERP RS		5.3
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Varity_R		0.95
gMVP		1.0
Mutation Taster		=10/90	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs2130205866; hg19: chr8-144898911;