3-33798921-C-T

Variant names:

• chr3-33798921-C-T
• rs374644579
• NM_013374.6:c.193C>T

Variant summary

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

The NM_013374.6(PDCD6IP):​c.193C>T​(p.Leu65Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,236 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PDCD6IP NM_013374.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.54

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDCD6IP	NM_013374.6	c.193C>T	p.Leu65Phe	missense_variant	Exon 1 of 18	ENST00000307296.8	NP_037506.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDCD6IP	ENST00000307296.8	c.193C>T	p.Leu65Phe	missense_variant	Exon 1 of 18	1	NM_013374.6	ENSP00000307387.3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152236 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1387272 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 681982

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152236 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74364

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Uncertain	0.057	T
BayesDel_noAF	Benign	-0.16
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T;.;T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Uncertain	0.62	D;D;D
MetaSVM	Benign	-0.69	T
MutationAssessor	Uncertain	2.8	M;M;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.4	D;D;D
REVEL	Uncertain	0.31
Sift	Uncertain	0.0040	D;D;D
Sift4G	Uncertain	0.0070	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.55
MutPred		0.63		Loss of glycosylation at K60 (P = 0.0312);Loss of glycosylation at K60 (P = 0.0312);Loss of glycosylation at K60 (P = 0.0312);
MVP		0.47
MPC		0.73
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.92
gMVP		0.12

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs374644579; hg19: chr3-33840413;