rs1554642573

Variant names:

• chr8-143817402-AG-GGGGCTGGGCCAGGGTCAA
• rs1554642573
• NM_078480.3:c.1072_1073delCTinsTTGACCCTGGCCCAGCCCC

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_078480.3(PUF60):​c.1072_1073delCTinsTTGACCCTGGCCCAGCCCC​(p.Thr359ArgfsTer26) variant causes a frameshift, missense change. 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 INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PUF60 NM_078480.3 frameshift, missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.94
• 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 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 8-143817402-AG-GGGGCTGGGCCAGGGTCAA is Pathogenic according to our data. Variant chr8-143817402-AG-GGGGCTGGGCCAGGGTCAA is described in ClinVar as Pathogenic. ClinVar VariationId is 520432.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.1072_1073delCTinsTTGACCCTGGCCCAGCCCC	p.Thr359ArgfsTer26	frameshift missense	Exon 10 of 12	NP_510965.1	Q9UHX1-1
	PUF60	NM_001362895.2		c.1183_1184delCTinsTTGACCCTGGCCCAGCCCC	p.Thr396ArgfsTer26	frameshift missense	Exon 11 of 13	NP_001349824.1	E9PL19
	PUF60	NM_001362896.2		c.1183_1184delCTinsTTGACCCTGGCCCAGCCCC	p.Thr396ArgfsTer26	frameshift missense	Exon 11 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.1072_1073delCTinsTTGACCCTGGCCCAGCCCC	p.Thr359ArgfsTer26	frameshift missense	Exon 10 of 12	ENSP00000434359.1	Q9UHX1-1
	PUF60	ENST00000349157.10	TSL:1	c.1021_1022delCTinsTTGACCCTGGCCCAGCCCC	p.Thr342ArgfsTer26	frameshift missense	Exon 9 of 11	ENSP00000322036.7	Q9UHX1-2
	PUF60	ENST00000453551.6	TSL:1	c.943_944delCTinsTTGACCCTGGCCCAGCCCC	p.Thr316ArgfsTer26	frameshift missense	Exon 10 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: Pathogenic

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.9

Splicing

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

Other links and lift over

dbSNP: rs1554642573; hg19: chr8-144899572;