3-33842000-G-A

Position:

chr3-33842000-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP3BP4_StrongBP6_Very_StrongBS1BS2

The NM_013374.6(PDCD6IP):c.1285G>A(p.Gly429Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0132 in 1,608,996 control chromosomes in the GnomAD database, including 182 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.0088 ( 11 hom., cov: 32)

Exomes 𝑓: 0.014 ( 171 hom. )

Consequence

PDCD6IP
NM_013374.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 10.0

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, Cadd, Eigen, FATHMM_MKL, MutationAssessor, phyloP100way_vertebrate, PROVEAN [when BayesDel_addAF, BayesDel_noAF, max_spliceai, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.010783076).

BP6

Variant 3-33842000-G-A is Benign according to our data. Variant chr3-33842000-G-A is described in ClinVar as [Benign]. Clinvar id is 777771.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.0137 (19959/1456728) while in subpopulation NFE AF= 0.0169 (18706/1107400). AF 95% confidence interval is 0.0167. There are 171 homozygotes in gnomad4_exome. There are 9812 alleles in male gnomad4_exome subpopulation. Median coverage is 28. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDCD6IP	NM_013374.6 link	c.1285G>A	p.Gly429Ser	missense_variant	10/18	ENST00000307296.8	NP_037506.2	Q8WUM4-1
PDCD6IP	NM_001162429.3 link	c.1300G>A	p.Gly434Ser	missense_variant	10/18		NP_001155901.1	Q8WUM4-2
PDCD6IP	XM_011533252.2 link	c.730G>A	p.Gly244Ser	missense_variant	10/18		XP_011531554.1
PDCD6IP	XM_047447042.1 link	c.730G>A	p.Gly244Ser	missense_variant	9/17		XP_047302998.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDCD6IP	ENST00000307296.8 link	c.1285G>A	p.Gly429Ser	missense_variant	10/18	1	NM_013374.6	ENSP00000307387.3		Q8WUM4-1

Frequencies

GnomAD3 genomes

AF:

0.00883

AC:

1344

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00290

Gnomad AMI

AF:

0.0471

Gnomad AMR

AF:

0.00530

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00187

Gnomad FIN

AF:

0.00302

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0153

Gnomad OTH

AF:

0.00717

GnomAD3 exomes

AF:

0.00746

AC:

1873

AN:

250984

Hom.:

AF XY:

0.00778

AC XY:

1056

AN XY:

135656

show subpopulations

Gnomad AFR exome

AF:

0.00191

Gnomad AMR exome

AF:

0.00269

Gnomad ASJ exome

AF:

0.000694

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00248

Gnomad FIN exome

AF:

0.00263

Gnomad NFE exome

AF:

0.0138

Gnomad OTH exome

AF:

0.00703

GnomAD4 exome

AF:

0.0137

AC:

19959

AN:

1456728

Hom.:

171

Cov.:

AF XY:

0.0135

AC XY:

9812

AN XY:

725008

show subpopulations

Gnomad4 AFR exome

AF:

0.00219

Gnomad4 AMR exome

AF:

0.00289

Gnomad4 ASJ exome

AF:

0.000882

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00289

Gnomad4 FIN exome

AF:

0.00309

Gnomad4 NFE exome

AF:

0.0169

Gnomad4 OTH exome

AF:

0.00988

GnomAD4 genome

AF:

0.00883

AC:

1344

AN:

152268

Hom.:

Cov.:

AF XY:

0.00787

AC XY:

586

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.00289

Gnomad4 AMR

AF:

0.00530

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00187

Gnomad4 FIN

AF:

0.00302

Gnomad4 NFE

AF:

0.0153

Gnomad4 OTH

AF:

0.00710

Alfa

AF:

0.0117

Hom.:

Bravo

AF:

0.00859

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.0131

AC:

113

ExAC

AF:

0.00762

AC:

925

EpiCase

AF:

0.0138

EpiControl

AF:

0.0118

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 15, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.22

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.21

T;.

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

D;D

MetaRNN

Benign

0.011

T;T

MetaSVM

Benign

-0.56

MutationAssessor

Pathogenic

3.1

M;.

PrimateAI

Uncertain

0.60

PROVEAN

Pathogenic

-5.9

D;D

REVEL

Uncertain

0.39

Sift

Uncertain

0.0040

D;D

Sift4G

Uncertain

0.0080

D;D

Polyphen

0.99

D;.

Vest4

0.84

MVP

0.67

MPC

1.0

ClinPred

0.054

GERP RS

4.5

Varity_R

0.97

gMVP

0.74

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over