ENST00000507735.6:c.395G>A

Variant names:

• chr4-168878286-G-A
• rs543821321
• ENST00000507735.6:c.395G>A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The ENST00000507735.6(PALLD):​c.395G>A​(p.Arg132His) variant causes a missense change. The variant allele was found at a frequency of 0.00128 in 1,526,406 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R132G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0015 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (5 hom.)
• Consequence: PALLD ENST00000507735.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.30

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007863641).
• BP6: Variant 4-168878286-G-A is Benign according to our data. Variant chr4-168878286-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 136006.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-168878286-G-A is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 230 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PALLD	NM_001166108.2	c.1965-12636G>A		intron_variant	Intron 10 of 21	ENST00000505667.6	NP_001159580.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PALLD	ENST00000505667.6	c.1965-12636G>A		intron_variant	Intron 10 of 21	1	NM_001166108.2	ENSP00000425556.1

Frequencies

GnomAD3 genomes AF: 0.00151 AC: 230 AN: 151896 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000459

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00397

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00249

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00116 AC: 141 AN: 121558 Hom.: 1 AF XY: 0.00117 AC XY: 78 AN XY: 66762

Gnomad AFR exome AF: 0.000201

Gnomad AMR exome AF: 0.000424

Gnomad ASJ exome AF: 0.000510

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00141

Gnomad FIN exome AF: 0.00412

Gnomad NFE exome AF: 0.00155

Gnomad OTH exome AF: 0.00107

GnomAD4 exome AF: 0.00125 AC: 1722 AN: 1374400 Hom.: 5 Cov.: 46 AF XY: 0.00126 AC XY: 853 AN XY: 677982

Gnomad4 AFR exome AF: 0.000131

Gnomad4 AMR exome AF: 0.000284

Gnomad4 ASJ exome AF: 0.000442

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00119

Gnomad4 FIN exome AF: 0.00383

Gnomad4 NFE exome AF: 0.00132

Gnomad4 OTH exome AF: 0.00101

GnomAD4 genome AF: 0.00151 AC: 230 AN: 152006 Hom.: 1 Cov.: 32 AF XY: 0.00141 AC XY: 105 AN XY: 74310

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00397

Gnomad4 NFE AF: 0.00249

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00302 Hom.: 0

Bravo AF: 0.000918

ExAC AF: 0.00117 AC: 21

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Jan 14, 2014

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Pancreatic adenocarcinoma Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

May 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PALLD: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	22
DANN	Uncertain	1.0
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.0079	T
MetaSVM	Benign	-0.97	T
PROVEAN	Benign	-0.89	N
REVEL	Benign	0.080
Sift	Uncertain	0.025	D
Sift4G	Benign	0.076	T
Vest4		0.15
MVP		0.56
ClinPred		0.028	T
GERP RS		4.4

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: rs543821321; hg19: chr4-169799437;