rs398123001

Positions:

• chr8-143818378-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Moderate

The NM_078480.3(PUF60):​c.505C>T​(p.His169Tyr) 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. 12/21 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:2
• Conservation: PhyloP100: 9.78

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a domain RRM 1 (size 78) in uniprot entity PUF60_HUMAN there are 11 pathogenic changes around while only 0 benign (100%) in NM_078480.3
• 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). GenCC has associacion of gene with 8q24.3 microdeletion syndrome, syndromic intellectual disability.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.931
• PP5: Variant 8-143818378-G-A is Pathogenic according to our data. Variant chr8-143818378-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 92112.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-143818378-G-A is described in UniProt as null. Variant chr8-143818378-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PUF60	NM_078480.3	c.505C>T	p.His169Tyr	missense_variant	6/12	ENST00000526683.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PUF60	ENST00000526683.6	c.505C>T	p.His169Tyr	missense_variant	6/12	1	NM_078480.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

8q24.3 microdeletion syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Sep 25, 2021	ACMG classification criteria: PS3 supporting, PS4 supporting, PM2 moderate, PM6 supporting, PP2 supporting, PP3 supporting -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 07, 2013	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T;.;.;.;.;.;.;T;.;T
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.16	D
MutationAssessor	Benign	1.5	L;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-5.6	D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D;D;D;.;D;.;.
Polyphen		1.0	D;.;.;P;D;.;.;.;.;.
Vest4		0.91
MutPred		0.81		Loss of disorder (P = 0.0884);.;.;.;.;.;.;.;.;.;
MVP		0.92
MPC		3.4
ClinPred		0.99	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.88
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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

Other links and lift over

dbSNP: rs398123001; hg19: chr8-144900548;