rs62333013

chr4-168878297-A-Gchr4-168878297-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000507735.6(PALLD):c.406A>G(p.Ser136Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.613 in 1,525,872 control chromosomes in the GnomAD database, including 295,098 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S136R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.51 (22843 hom., cov: 33)
  • Exomes 𝑓: 0.62 (272255 hom.)
• Consequence: PALLD ENST00000507735.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.339

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]

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.1354703E-6).
• BP6: Variant 4-168878297-A-G is Benign according to our data. Variant chr4-168878297-A-G is described in ClinVar as [Benign]. Clinvar id is 182793.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.645 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PALLD	NM_001166108.2	c.1965-12625A>G		intron_variant		ENST00000505667.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PALLD	ENST00000505667.6	c.1965-12625A>G		intron_variant		1	NM_001166108.2	A2

Frequencies

GnomAD3 genomes AF: 0.507 AC: 77069 AN: 151876 Hom.: 22832 Cov.: 33

Gnomad AFR AF: 0.177

Gnomad AMI AF: 0.604

Gnomad AMR AF: 0.554

Gnomad ASJ AF: 0.612

Gnomad EAS AF: 0.536

Gnomad SAS AF: 0.663

Gnomad FIN AF: 0.730

Gnomad MID AF: 0.532

Gnomad NFE AF: 0.643

Gnomad OTH AF: 0.525

GnomAD3 exomes AF: 0.613 AC: 74166 AN: 121080 Hom.: 23566 AF XY: 0.618 AC XY: 41053 AN XY: 66452

Gnomad AFR exome AF: 0.136

Gnomad AMR exome AF: 0.626

Gnomad ASJ exome AF: 0.621

Gnomad EAS exome AF: 0.523

Gnomad SAS exome AF: 0.661

Gnomad FIN exome AF: 0.734

Gnomad NFE exome AF: 0.640

Gnomad OTH exome AF: 0.602

GnomAD4 exome AF: 0.624 AC: 857519 AN: 1373882 Hom.: 272255 Cov.: 56 AF XY: 0.627 AC XY: 424889 AN XY: 677634

Gnomad4 AFR exome AF: 0.152

Gnomad4 AMR exome AF: 0.620

Gnomad4 ASJ exome AF: 0.617

Gnomad4 EAS exome AF: 0.535

Gnomad4 SAS exome AF: 0.664

Gnomad4 FIN exome AF: 0.730

Gnomad4 NFE exome AF: 0.636

Gnomad4 OTH exome AF: 0.595

GnomAD4 genome AF: 0.507 AC: 77091 AN: 151990 Hom.: 22843 Cov.: 33 AF XY: 0.515 AC XY: 38272 AN XY: 74310

Gnomad4 AFR AF: 0.176

Gnomad4 AMR AF: 0.554

Gnomad4 ASJ AF: 0.612

Gnomad4 EAS AF: 0.536

Gnomad4 SAS AF: 0.664

Gnomad4 FIN AF: 0.730

Gnomad4 NFE AF: 0.643

Gnomad4 OTH AF: 0.527

Alfa AF: 0.597 Hom.: 6471

Bravo AF: 0.479

TwinsUK AF: 0.656 AC: 2431

ALSPAC AF: 0.631 AC: 2433

ExAC AF: 0.540 AC: 8133

Asia WGS AF: 0.622 AC: 2160 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 30, 2020	This alteration is classified as 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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Pancreatic cancer, susceptibility to, 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Pancreatic adenocarcinoma Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.63
Cadd	Benign	1.9
Dann	Benign	0.75
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.039	N
LIST_S2	Benign	0.34	T
MetaRNN	Benign	0.0000031	T
MetaSVM	Benign	-0.96	T
MutationTaster	Benign	1.0	P;P;P;P;P
PROVEAN	Benign	-0.94	N
REVEL	Benign	0.094
Sift	Benign	0.75	T
Sift4G	Benign	0.37	T
Vest4		0.015
ClinPred		0.0034	T
GERP RS		-5.0

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

Other links and lift over

dbSNP: rs62333013; hg19: chr4-169799448; COSMIC: COSV54977122;