rs121908291

Positions:

chr4-168878306-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4BP6BS2

The NM_001166110.2(PALLD):c.415C>T(p.Pro139Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0008 in 1,527,100 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00086 ( 4 hom. )

Consequence

PALLD
NM_001166110.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2O:1

Conservation

PhyloP100: 5.40

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:):

CBR4 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 Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.34723958).

BP6

Variant 4-168878306-C-T is Benign according to our data. Variant chr4-168878306-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2572.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=1}.

BS2

High AC in GnomAd4 at 37 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PALLD	NM_001166108.2 linkuse as main transcript	c.1965-12616C>T		intron_variant		ENST00000505667.6	NP_001159580.1	Q8WX93-9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PALLD	ENST00000505667.6 linkuse as main transcript	c.1965-12616C>T		intron_variant		1	NM_001166108.2	ENSP00000425556.1		Q8WX93-9

Frequencies

GnomAD3 genomes

AF:

0.000243

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.000470

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000205

AC:

AN:

122174

Hom.:

AF XY:

0.000239

AC XY:

AN XY:

67048

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000467

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000486

Gnomad OTH exome

AF:

0.000531

GnomAD4 exome

AF:

0.000862

AC:

1185

AN:

1374906

Hom.:

Cov.:

AF XY:

0.000843

AC XY:

572

AN XY:

678180

show subpopulations

Gnomad4 AFR exome

AF:

0.000163

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000512

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00107

Gnomad4 OTH exome

AF:

0.000435

GnomAD4 genome

AF:

0.000243

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.0000965

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000470

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000299

Hom.:

Bravo

AF:

0.000249

ExAC

AF:

0.0000607

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 06, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 04, 2024	The c.415C>T (p.P139S) alteration is located in exon 2 (coding exon 1) of the PALLD gene. This alteration results from a C to T substitution at nucleotide position 415, causing the proline (P) at amino acid position 139 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Pancreatic adenocarcinoma

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 16, 2023

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 139 of the PALLD protein (p.Pro139Ser). This variant is present in population databases (rs121908291, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of PALLD-related conditions (PMID: 10454945, 11474289, 17194196, 17415588). It has also been observed to segregate with disease in related individuals. This variant is also known as 715C>T (Pro239Ser). ClinVar contains an entry for this variant (Variation ID: 2572). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects PALLD function (PMID: 17194196). 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. -

PALLD-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 26, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Pancreatic cancer, susceptibility to, 1

Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Jun 01, 2007

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.090

BayesDel_noAF

Uncertain

-0.030

CADD

Benign

DANN

Uncertain

1.0

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.77

M_CAP

Uncertain

0.22

MetaRNN

Benign

0.35

MetaSVM

Uncertain

0.53

PROVEAN

Uncertain

-3.4

REVEL

Uncertain

0.45

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.012

Vest4

0.38

MVP

0.70

ClinPred

0.21

GERP RS

4.6

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