3-33865759-A-T

Variant names:

• chr3-33865759-A-T
• rs9858195
• NM_013374.6:c.2432+329A>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_013374.6(PDCD6IP):​c.2432+329A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0381 in 152,284 control chromosomes in the GnomAD database, including 100 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.038 (100 hom., cov: 32)
• Consequence: PDCD6IP NM_013374.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.101
• 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 Gene-Disease associations (from GenCC):

• microcephaly 29, primary, autosomal recessive

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0381 (5807/152284) while in subpopulation AFR AF = 0.0485 (2017/41558). AF 95% confidence interval is 0.0468. There are 100 homozygotes in GnomAd4. There are 2854 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 100 AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDCD6IP	NM_013374.6	MANE Select	c.2432+329A>T		intron	N/A	NP_037506.2
	PDCD6IP	NM_001162429.3		c.2447+329A>T		intron	N/A	NP_001155901.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDCD6IP	ENST00000307296.8	TSL:1 MANE Select	c.2432+329A>T		intron	N/A	ENSP00000307387.3
	PDCD6IP	ENST00000457054.6	TSL:1	c.2447+329A>T		intron	N/A	ENSP00000411825.2
	PDCD6IP	ENST00000473593.1	TSL:2	n.422+329A>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0382 AC: 5806 AN: 152166 Hom.: 100 Cov.: 32

Gnomad AFR AF: 0.0486

Gnomad AMI AF: 0.102

Gnomad AMR AF: 0.0306

Gnomad ASJ AF: 0.0112

Gnomad EAS AF: 0.0177

Gnomad SAS AF: 0.0280

Gnomad FIN AF: 0.0524

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0344

Gnomad OTH AF: 0.0321

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

GnomAD4 genome AF: 0.0381 AC: 5807 AN: 152284 Hom.: 100 Cov.: 32 AF XY: 0.0383 AC XY: 2854 AN XY: 74462

African (AFR) AF: 0.0485 AC: 2017 AN: 41558

American (AMR) AF: 0.0305 AC: 467 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0112 AC: 39 AN: 3470

East Asian (EAS) AF: 0.0175 AC: 91 AN: 5194

South Asian (SAS) AF: 0.0276 AC: 133 AN: 4824

European-Finnish (FIN) AF: 0.0524 AC: 556 AN: 10604

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0344 AC: 2342 AN: 68020

Other (OTH) AF: 0.0318 AC: 67 AN: 2110

Alfa AF: 0.0102 Hom.: 2

Bravo AF: 0.0366

Asia WGS AF: 0.0320 AC: 110 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	3.8
DANN	Benign	0.77
PhyloP100		0.10
Mutation Taster		=100/0	polymorphism

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: rs9858195; hg19: chr3-33907251;