rs1554642573

Variant names:

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

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PVS1 PM2 PP2 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. 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

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 Pathogenic. Variant got 13 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
• PP2: Missense variant in the PUF60 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 16 curated pathogenic missense variants (we use a threshold of 10). The gene has 6 curated benign missense variants. Gene score misZ: 4.4358 (above the threshold of 3.09). Trascript score misZ: 4.9183 (above the threshold of 3.09). GenCC associations: The gene is linked to 8q24.3 microdeletion syndrome, syndromic intellectual disability.
• PP5: Variant 8-143817402-AG-GGGGCTGGGCCAGGGTCAA is Pathogenic according to our data. Variant chr8-143817402-AG-GGGGCTGGGCCAGGGTCAA is described in ClinVar as [Pathogenic]. Clinvar id is 520432.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PUF60	NM_078480.3	c.1072_1073delCTinsTTGACCCTGGCCCAGCCCC	p.Thr359ArgfsTer26	frameshift_variant, missense_variant	Exon 10 of 12	ENST00000526683.6	NP_510965.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PUF60	ENST00000526683.6	c.1072_1073delCTinsTTGACCCTGGCCCAGCCCC	p.Thr359ArgfsTer26	frameshift_variant, missense_variant	Exon 10 of 12	1	NM_078480.3	ENSP00000434359.1

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

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

8q24.3 microdeletion syndrome Pathogenic:1

Feb 16, 2018

Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

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Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554642573; hg19: chr8-144899572;