3-33841994-C-A

Position:

• chr3-33841994-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_013374.6(PDCD6IP):​c.1279C>A​(p.Gln427Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000275 in 1,454,024 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: PDCD6IP NM_013374.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.85

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.068112135).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDCD6IP	NM_013374.6	c.1279C>A	p.Gln427Lys	missense_variant	10/18	ENST00000307296.8	NP_037506.2
PDCD6IP	NM_001162429.3	c.1294C>A	p.Gln432Lys	missense_variant	10/18		NP_001155901.1
PDCD6IP	XM_011533252.2	c.724C>A	p.Gln242Lys	missense_variant	10/18		XP_011531554.1
PDCD6IP	XM_047447042.1	c.724C>A	p.Gln242Lys	missense_variant	9/17		XP_047302998.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDCD6IP	ENST00000307296.8	c.1279C>A	p.Gln427Lys	missense_variant	10/18	1	NM_013374.6	ENSP00000307387.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000275 AC: 4 AN: 1454024 Hom.: 0 Cov.: 27 AF XY: 0.00000276 AC XY: 2 AN XY: 723896

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000362

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 16, 2023

The c.1294C>A (p.Q432K) alteration is located in exon 10 (coding exon 10) of the PDCD6IP gene. This alteration results from a C to A substitution at nucleotide position 1294, causing the glutamine (Q) at amino acid position 432 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	20
DANN	Benign	0.66
DEOGEN2	Benign	0.0060	T;.
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.78	T;T
M_CAP	Benign	0.0089	T
MetaRNN	Benign	0.068	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.58	N;.
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.080	N;N
REVEL	Benign	0.090
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0010	B;.
Vest4		0.24
MutPred		0.38		Gain of methylation at Q427 (P = 0.0098);.;
MVP		0.41
MPC		0.39
ClinPred		0.91	D
GERP RS		4.7
Varity_R		0.28
gMVP		0.38

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-33883486;