rs200020758

Variant names:

• chr4-168878233-A-ACCG
• rs200020758
• ENST00000507735.6:c.347_349dupCGC

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PM4_Supporting BP6_Very_Strong BS1 BS2

The NM_001166110.2(PALLD):​c.347_349dupCGC​(p.Pro116dup) variant causes a disruptive inframe insertion change. The variant allele was found at a frequency of 0.00166 in 1,497,616 control chromosomes in the GnomAD database, including 36 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0099 (19 hom., cov: 32)
  • Exomes 𝑓: 0.00080 (17 hom.)
• Consequence: PALLD NM_001166110.2 disruptive_inframe_insertion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 5.32

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 -15 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_001166110.2. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 4-168878233-A-ACCG is Benign according to our data. Variant chr4-168878233-A-ACCG is described in ClinVar as [Benign]. Clinvar id is 416233.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00987 (1399/141794) while in subpopulation AFR AF= 0.0346 (1304/37698). AF 95% confidence interval is 0.033. There are 19 homozygotes in gnomad4. There are 668 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1399 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PALLD	NM_001166108.2	c.1965-12684_1965-12682dupCGC		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.1965-12684_1965-12682dupCGC		intron_variant	Intron 10 of 21	1	NM_001166108.2	ENSP00000425556.1

Frequencies

GnomAD3 genomes AF: 0.00983 AC: 1393 AN: 141710 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.0345

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00451

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000240

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000260

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00111 AC: 127 AN: 113988 Hom.: 5 AF XY: 0.000715 AC XY: 45 AN XY: 62916

Gnomad AFR exome AF: 0.0256

Gnomad AMR exome AF: 0.00116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000489

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000702

Gnomad OTH exome AF: 0.00172

GnomAD4 exome AF: 0.000800 AC: 1084 AN: 1355822 Hom.: 17 Cov.: 46 AF XY: 0.000670 AC XY: 448 AN XY: 669068

Gnomad4 AFR exome AF: 0.0297

Gnomad4 AMR exome AF: 0.00174

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000520

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000347

Gnomad4 OTH exome AF: 0.00208

GnomAD4 genome AF: 0.00987 AC: 1399 AN: 141794 Hom.: 19 Cov.: 32 AF XY: 0.00970 AC XY: 668 AN XY: 68884

Gnomad4 AFR AF: 0.0346

Gnomad4 AMR AF: 0.00450

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000240

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000260

Gnomad4 OTH AF: 0.00663

Alfa AF: 0.00554 Hom.: 0

Asia WGS AF: 0.00145 AC: 5 AN: 3466

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Oct 29, 2024

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PALLD-related disorder Benign:1

Oct 10, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs200020758; hg19: chr4-169799384;