rs1554641549

Variant names:

• chr8-143816612-GGATGGCCTTAT-G
• rs1554641549
• NM_078480.3:c.1577_1587delATAAGGCCATC

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Strong PP5_Moderate

The NM_078480.3(PUF60):​c.1577_1587delATAAGGCCATC​(p.His526ProfsTer16) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PUF60 NM_078480.3 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.12
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 5 pathogenic variants in the truncated region.
• PP5: Variant 8-143816612-GGATGGCCTTAT-G is Pathogenic according to our data. Variant chr8-143816612-GGATGGCCTTAT-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 425568.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.1577_1587delATAAGGCCATC	p.His526ProfsTer16	frameshift	Exon 12 of 12	NP_510965.1
	PUF60	NM_001362895.2		c.1688_1698delATAAGGCCATC	p.His563ProfsTer16	frameshift	Exon 13 of 13	NP_001349824.1
	PUF60	NM_001362896.2		c.1688_1698delATAAGGCCATC	p.His563ProfsTer16	frameshift	Exon 13 of 13	NP_001349825.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PUF60	ENST00000526683.6	TSL:1 MANE Select	c.1577_1587delATAAGGCCATC	p.His526ProfsTer16	frameshift	Exon 12 of 12	ENSP00000434359.1
	PUF60	ENST00000349157.10	TSL:1	c.1526_1536delATAAGGCCATC	p.His509ProfsTer16	frameshift	Exon 11 of 11	ENSP00000322036.7
	PUF60	ENST00000453551.6	TSL:1	c.1448_1458delATAAGGCCATC	p.His483ProfsTer16	frameshift	Exon 12 of 12	ENSP00000402953.2

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 as Germline

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.1
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs1554641549; hg19: chr8-144898782;