3-33798874-T-TGCGCC

Variant names:

• chr3-33798874-T-TGCGCC
• NM_013374.6:c.154_158dupGCCGC

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP5

The NM_013374.6(PDCD6IP):​c.154_158dupGCCGC​(p.Val54ProfsTer18) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PDCD6IP NM_013374.6 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.21
• Publications: 1 publications found

Genes affected

PDCD6IP (HGNC:8766): (programmed cell death 6 interacting protein) This gene encodes a protein that functions within the ESCRT pathway in the abscission stage of cytokinesis, in intralumenal endosomal vesicle formation, and in enveloped virus budding. Studies using mouse cells have shown that overexpression of this protein can block apoptosis. In addition, the product of this gene binds to the product of the PDCD6 gene, a protein required for apoptosis, in a calcium-dependent manner. This gene product also binds to endophilins, proteins that regulate membrane shape during endocytosis. Overexpression of this gene product and endophilins results in cytoplasmic vacuolization, which may be partly responsible for the protection against cell death. Several alternatively spliced transcript variants encoding different isoforms have been found for this gene. Related pseudogenes have been identified on chromosome 15. [provided by RefSeq, Jan 2012]

PDCD6IP-DT (HGNC:55244): (PDCD6IP divergent transcript)

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-33798874-T-TGCGCC is Pathogenic according to our data. Variant chr3-33798874-T-TGCGCC is described in ClinVar as Pathogenic. ClinVar VariationId is 1706482.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013374.6. 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
	PDCD6IP	NM_013374.6	MANE Select	c.154_158dupGCCGC	p.Val54ProfsTer18	frameshift	Exon 1 of 18	NP_037506.2
	PDCD6IP	NM_001162429.3		c.154_158dupGCCGC	p.Val54ProfsTer18	frameshift	Exon 1 of 18	NP_001155901.1	Q8WUM4-2
	PDCD6IP	NM_001256192.2		c.154_158dupGCCGC	p.Val54ProfsTer18	frameshift	Exon 1 of 6	NP_001243121.1	Q8WUM4-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDCD6IP	ENST00000307296.8	TSL:1 MANE Select	c.154_158dupGCCGC	p.Val54ProfsTer18	frameshift	Exon 1 of 18	ENSP00000307387.3	Q8WUM4-1
	PDCD6IP	ENST00000457054.6	TSL:1	c.154_158dupGCCGC	p.Val54ProfsTer18	frameshift	Exon 1 of 18	ENSP00000411825.2	Q8WUM4-2
	PDCD6IP	ENST00000965906.1		c.154_158dupGCCGC	p.Val54ProfsTer18	frameshift	Exon 1 of 19	ENSP00000635965.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Microcephaly 29, primary, autosomal recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.2

Splicing

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

Other links and lift over

hg19: chr3-33840366;