rs551420048

Positions:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The ENST00000505667.6(PALLD):c.2902G>A(p.Val968Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000317 in 1,609,324 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V968G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000040 ( 0 hom., cov: 25)

Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

PALLD
ENST00000505667.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 1.77

Variant links:

Genes affected

PALLD (HGNC:17068): (palladin, cytoskeletal associated protein) This gene encodes a cytoskeletal protein that is required for organizing the actin cytoskeleton. The protein is a component of actin-containing microfilaments, and it is involved in the control of cell shape, adhesion, and contraction. Polymorphisms in this gene are associated with a susceptibility to pancreatic cancer type 1, and also with a risk for myocardial infarction. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2009]

PALLD links:

CBR4 (HGNC:25891): (carbonyl reductase 4) Enables several functions, including 3-oxoacyl-[acyl-carrier-protein] reductase (NADPH) activity; NADPH binding activity; and NADPH dehydrogenase (quinone) activity. Involved in fatty acid biosynthetic process; glycoside metabolic process; and protein tetramerization. Located in mitochondrial matrix. Part of oxidoreductase complex. [provided by Alliance of Genome Resources, Apr 2022]

CBR4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.026730865).

BP6

Variant 4-168921585-G-A is Benign according to our data. Variant chr4-168921585-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 573918.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BS2

High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PALLD	NM_001166108.2 linkuse as main transcript	c.2902G>A	p.Val968Ile	missense_variant	18/22	ENST00000505667.6	NP_001159580.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PALLD	ENST00000505667.6 linkuse as main transcript	c.2902G>A	p.Val968Ile	missense_variant	18/22	1	NM_001166108.2	ENSP00000425556	A2	Q8WX93-9

Frequencies

GnomAD3 genomes

AF:

0.0000405

AC:

AN:

148086

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000684

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000675

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000297

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000520

AC:

AN:

249926

Hom.:

AF XY:

0.0000963

AC XY:

AN XY:

135004

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000548

Gnomad SAS exome

AF:

0.000230

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000886

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000308

AC:

AN:

1461120

Hom.:

Cov.:

AF XY:

0.0000385

AC XY:

AN XY:

726790

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000672

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000279

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000144

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000405

AC:

AN:

148204

Hom.:

Cov.:

AF XY:

0.0000695

AC XY:

AN XY:

71924

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000683

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000675

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000297

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Pancreatic adenocarcinoma

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 04, 2023

Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 464 of the PALLD protein (p.Val464Ile). This variant is present in population databases (rs551420048, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with PALLD-related conditions. ClinVar contains an entry for this variant (Variation ID: 573918). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 25, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.50

CADD

Benign

0.93

DANN

Benign

0.73

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.41

LIST_S2

Benign

0.75

T;T;T;T

M_CAP

Benign

0.010

MetaRNN

Benign

0.027

T;T;T;T

MetaSVM

Benign

-0.95

MutationTaster

Benign

1.0

N;N;N;N;N

PrimateAI

Benign

0.25

PROVEAN

Benign

0.11

N;N;N;N

REVEL

Benign

0.15

Sift

Benign

1.0

T;T;T;T

Sift4G

Benign

1.0

T;T;T;T

Vest4

0.22

MVP

0.18

MPC

0.16

ClinPred

0.016

GERP RS

-1.8

gMVP

0.085

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