rs114593924

chr4-168925017-T-C

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001166108.2(PALLD):c.3297T>C(p.Tyr1099=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00303 in 1,614,102 control chromosomes in the GnomAD database, including 97 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0053 (12 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (85 hom.)
• Consequence: PALLD NM_001166108.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.390

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 4-168925017-T-C is Benign according to our data. Variant chr4-168925017-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 136000.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-168925017-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.39 with no splicing effect.
• BS2: High AC in GnomAd at 812 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PALLD	NM_001166108.2	c.3297T>C	p.Tyr1099=	synonymous_variant	20/22	ENST00000505667.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PALLD	ENST00000505667.6	c.3297T>C	p.Tyr1099=	synonymous_variant	20/22	1	NM_001166108.2	A2

Frequencies

GnomAD3 genomes AF: 0.00534 AC: 812 AN: 152202 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.000289

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.0138

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.0575

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00165

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00634 AC: 1593 AN: 251136 Hom.: 37 AF XY: 0.00626 AC XY: 849 AN XY: 135716

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.0130

Gnomad EAS exome AF: 0.00114

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0552

Gnomad NFE exome AF: 0.00150

Gnomad OTH exome AF: 0.00930

GnomAD4 exome AF: 0.00279 AC: 4075 AN: 1461782 Hom.: 85 Cov.: 32 AF XY: 0.00272 AC XY: 1980 AN XY: 727204

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.0132

Gnomad4 EAS exome AF: 0.00242

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.0547

Gnomad4 NFE exome AF: 0.000406

Gnomad4 OTH exome AF: 0.00402

GnomAD4 genome AF: 0.00532 AC: 811 AN: 152320 Hom.: 12 Cov.: 32 AF XY: 0.00768 AC XY: 572 AN XY: 74484

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.0138

Gnomad4 EAS AF: 0.00173

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.0575

Gnomad4 NFE AF: 0.00165

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00288 Hom.: 0

Bravo AF: 0.000839

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 02, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 12, 2022	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. -

Pancreatic cancer, susceptibility to, 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Pancreatic adenocarcinoma Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 26, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Mar 01, 2022

PALLD: BP4, BP7, BS1, BS2 -

PALLD-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 12, 2019

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
Cadd	Benign	0.91
Dann	Benign	0.56

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: rs114593924; hg19: chr4-169846168;