NM_001020658.2:c.3267_3270delTCAC

Variant names:

• chr1-30936807-CGTGA-C
• rs2124378402
• NM_001020658.2:c.3267_3270delTCAC

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001020658.2(PUM1):​c.3267_3270delTCAC​(p.His1090ProfsTer16) 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 Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 30)
• Consequence: PUM1 NM_001020658.2 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:2
• Conservation: PhyloP100: 10.0
• Publications: 0 publications found

Genes affected

PUM1 (HGNC:14957): (pumilio RNA binding family member 1) This gene encodes a member of the PUF family, evolutionarily conserved RNA-binding proteins related to the Pumilio proteins of Drosophila and the fem-3 mRNA binding factor proteins of C. elegans. The encoded protein contains a sequence-specific RNA binding domain comprised of eight repeats and N- and C-terminal flanking regions, and serves as a translational regulator of specific mRNAs by binding to their 3' untranslated regions. The evolutionarily conserved function of the encoded protein in invertebrates and lower vertebrates suggests that the human protein may be involved in translational regulation of embryogenesis, and cell development and differentiation. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

PUM1 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with motor abnormalities, seizures, and facial dysmorphism

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• spinocerebellar ataxia 47

  Inheritance: AD Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, Illumina

ENSG00000307336 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 11 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 1-30936807-CGTGA-C is Pathogenic according to our data. Variant chr1-30936807-CGTGA-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1064828.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001020658.2. 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
	PUM1	NM_001020658.2	MANE Select	c.3267_3270delTCAC	p.His1090ProfsTer16	frameshift	Exon 21 of 22	NP_001018494.1	Q14671-3
	PUM1	NM_014676.3		c.3261_3264delTCAC	p.His1088ProfsTer16	frameshift	Exon 21 of 22	NP_055491.1	Q14671-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PUM1	ENST00000426105.7	TSL:1 MANE Select	c.3267_3270delTCAC	p.His1090ProfsTer16	frameshift	Exon 21 of 22	ENSP00000391723.2	Q14671-3
	PUM1	ENST00000373741.8	TSL:1	c.3375_3378delTCAC	p.His1126ProfsTer16	frameshift	Exon 21 of 22	ENSP00000362846.4	Q5T1Z8
	PUM1	ENST00000257075.9	TSL:1	c.3261_3264delTCAC	p.His1088ProfsTer16	frameshift	Exon 21 of 22	ENSP00000257075.5	Q14671-1

Frequencies

GnomAD3 genomes Cov.: 30

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

GnomAD4 genome Cov.: 30

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	1	-	not provided (3)
-	1	-	Neurodevelopmental disorder (1)
1	-	-	Spinocerebellar ataxia 47 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		10

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: rs2124378402; hg19: chr1-31409654;