rs1085307137

Variant names:

• chr8-143818408-C-T
• rs1085307137
• NM_078480.3:c.475G>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 6P and 1B. PM1 PM2 PP5_Moderate BP4

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
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.04
• Publications: 5 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: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a domain RRM 1 (size 78) in uniprot entity PUF60_HUMAN there are 10 pathogenic changes around while only 0 benign (100%) in NM_078480.3
• 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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PUF60	NM_078480.3	c.475G>A	p.Asp159Asn	missense_variant	Exon 6 of 12	ENST00000526683.6	NP_510965.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PUF60	ENST00000526683.6	c.475G>A	p.Asp159Asn	missense_variant	Exon 6 of 12	1	NM_078480.3	ENSP00000434359.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Jan 19, 2017

Bristol Genetics Laboratory, North Bristol NHS Trust

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.051	T;.;.;.;.;.;.;T;.;T
Eigen	Benign	-0.096
Eigen_PC	Benign	0.11
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.27	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L;.;.;.;.;.;.;.;.;.
PhyloP100		6.0
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	1.5	N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.14
Sift	Benign	0.92	T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T;T;.;T;.;.
Polyphen		0.060	B;.;.;B;B;.;.;.;.;.
Vest4		0.73
MutPred		0.45		Gain of MoRF binding (P = 0.059);.;.;.;.;.;.;.;.;.;
MVP		0.34
MPC		1.7
ClinPred		0.89	D
GERP RS		5.2
PromoterAI		-0.029	Neutral
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)

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

Other links and lift over

dbSNP: rs1085307137; hg19: chr8-144900578; COSMIC: COSV57594936; COSMIC: COSV57594936;