rs1554643473

Variant names:

• chr8-143818403-CAT-C
• rs1554643473
• NM_078480.3:c.478_479delAT

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_078480.3(PUF60):​c.478_479delAT​(p.Met160ValfsTer18) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PUF60 NM_078480.3 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: 9.16
• 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
• syndromic intellectual disability

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-143818403-CAT-C is Pathogenic according to our data. Variant chr8-143818403-CAT-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 520562.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PUF60	NM_078480.3	MANE Select	c.478_479delAT	p.Met160ValfsTer18	frameshift	Exon 6 of 12	NP_510965.1	Q9UHX1-1
	PUF60	NM_001362895.2		c.589_590delAT	p.Met197ValfsTer18	frameshift	Exon 7 of 13	NP_001349824.1	E9PL19
	PUF60	NM_001362896.2		c.589_590delAT	p.Met197ValfsTer18	frameshift	Exon 7 of 13	NP_001349825.1	E9PL19

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PUF60	ENST00000526683.6	TSL:1 MANE Select	c.478_479delAT	p.Met160ValfsTer18	frameshift	Exon 6 of 12	ENSP00000434359.1	Q9UHX1-1
	PUF60	ENST00000349157.10	TSL:1	c.427_428delAT	p.Met143ValfsTer18	frameshift	Exon 5 of 11	ENSP00000322036.7	Q9UHX1-2
	PUF60	ENST00000453551.6	TSL:1	c.349_350delAT	p.Met117ValfsTer18	frameshift	Exon 6 of 12	ENSP00000402953.2	Q9UHX1-3

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Inborn genetic diseases (1)
-	-	-	8q24.3 microdeletion syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.2

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: rs1554643473; hg19: chr8-144900573;