NM_013374.6:c.193C>A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_013374.6(PDCD6IP):​c.193C>A​(p.Leu65Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000144 in 1,387,272 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PDCD6IP NM_013374.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.54
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37153703).

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.193C>A	p.Leu65Ile	missense	Exon 1 of 18	NP_037506.2
	PDCD6IP	NM_001162429.3		c.193C>A	p.Leu65Ile	missense	Exon 1 of 18	NP_001155901.1	Q8WUM4-2
	PDCD6IP	NM_001256192.2		c.193C>A	p.Leu65Ile	missense	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.193C>A	p.Leu65Ile	missense	Exon 1 of 18	ENSP00000307387.3	Q8WUM4-1
	PDCD6IP	ENST00000457054.6	TSL:1	c.193C>A	p.Leu65Ile	missense	Exon 1 of 18	ENSP00000411825.2	Q8WUM4-2
	PDCD6IP	ENST00000965906.1		c.193C>A	p.Leu65Ile	missense	Exon 1 of 19	ENSP00000635965.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000144 AC: 2 AN: 1387272 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 681982

African (AFR) AF: 0.00 AC: 0 AN: 31288

American (AMR) AF: 0.00 AC: 0 AN: 35444

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25028

East Asian (EAS) AF: 0.00 AC: 0 AN: 35398

South Asian (SAS) AF: 0.00 AC: 0 AN: 78866

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48468

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4382

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1071162

Other (OTH) AF: 0.0000349 AC: 2 AN: 57236

GnomAD4 genome Cov.: 33

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Pathogenic	28
DANN	Benign	0.97
DEOGEN2	Benign	0.047	T
Eigen	Benign	0.11
Eigen_PC	Benign	0.11
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.096	D
MetaRNN	Benign	0.37	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
PhyloP100		5.5
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.23
Sift	Benign	0.039	D
Sift4G	Uncertain	0.057	T
Polyphen		0.85	P
Vest4		0.45
MutPred		0.61		Loss of glycosylation at K60 (P = 0.0312)
MVP		0.28
MPC		0.80
ClinPred		0.96	D
GERP RS		4.8
PromoterAI		0.21	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.80
gMVP		0.047
Mutation Taster		=60/40	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: rs374644579; hg19: chr3-33840413;