rs1059444

chr4-168913983-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001166108.2(PALLD):c.2679A>G(p.Arg893=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.101 in 1,611,468 control chromosomes in the GnomAD database, including 9,124 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1389 hom., cov: 32)
  • Exomes 𝑓: 0.098 (7735 hom.)
• Consequence: PALLD NM_001166108.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.523

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 4-168913983-A-G is Benign according to our data. Variant chr4-168913983-A-G is described in ClinVar as [Benign]. Clinvar id is 348043.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.523 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.194 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PALLD	NM_001166108.2	c.2679A>G	p.Arg893=	synonymous_variant	16/22	ENST00000505667.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PALLD	ENST00000505667.6	c.2679A>G	p.Arg893=	synonymous_variant	16/22	1	NM_001166108.2	A2

Frequencies

GnomAD3 genomes AF: 0.124 AC: 18837 AN: 152094 Hom.: 1386 Cov.: 32

Gnomad AFR AF: 0.198

Gnomad AMI AF: 0.0987

Gnomad AMR AF: 0.112

Gnomad ASJ AF: 0.187

Gnomad EAS AF: 0.0387

Gnomad SAS AF: 0.0531

Gnomad FIN AF: 0.0445

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.103

Gnomad OTH AF: 0.125

GnomAD3 exomes AF: 0.0916 AC: 23027 AN: 251416 Hom.: 1347 AF XY: 0.0901 AC XY: 12248 AN XY: 135884

Gnomad AFR exome AF: 0.201

Gnomad AMR exome AF: 0.0695

Gnomad ASJ exome AF: 0.186

Gnomad EAS exome AF: 0.0342

Gnomad SAS exome AF: 0.0513

Gnomad FIN exome AF: 0.0454

Gnomad NFE exome AF: 0.102

Gnomad OTH exome AF: 0.111

GnomAD4 exome AF: 0.0984 AC: 143631 AN: 1459256 Hom.: 7735 Cov.: 30 AF XY: 0.0971 AC XY: 70531 AN XY: 726090

Gnomad4 AFR exome AF: 0.202

Gnomad4 AMR exome AF: 0.0729

Gnomad4 ASJ exome AF: 0.183

Gnomad4 EAS exome AF: 0.0420

Gnomad4 SAS exome AF: 0.0517

Gnomad4 FIN exome AF: 0.0503

Gnomad4 NFE exome AF: 0.102

Gnomad4 OTH exome AF: 0.107

GnomAD4 genome AF: 0.124 AC: 18853 AN: 152212 Hom.: 1389 Cov.: 32 AF XY: 0.118 AC XY: 8821 AN XY: 74442

Gnomad4 AFR AF: 0.198

Gnomad4 AMR AF: 0.111

Gnomad4 ASJ AF: 0.187

Gnomad4 EAS AF: 0.0387

Gnomad4 SAS AF: 0.0533

Gnomad4 FIN AF: 0.0445

Gnomad4 NFE AF: 0.103

Gnomad4 OTH AF: 0.124

Alfa AF: 0.117 Hom.: 639

Bravo AF: 0.133

Asia WGS AF: 0.0430 AC: 150 AN: 3476

EpiCase AF: 0.114

EpiControl AF: 0.112

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pancreatic cancer, susceptibility to, 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified Benign:1

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. -

Pancreatic adenocarcinoma Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
Cadd	Benign	11
Dann	Benign	0.70

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: rs1059444; hg19: chr4-169835134; COSMIC: COSV54980401; COSMIC: COSV54980401;