rs201979617

Positions:

• chr4-168878227-G-GCCA
• chr4-168878227-G-GCCACCACCA

Variant summary

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

The ENST00000507735.6(PALLD):​c.342_344dup​(p.Pro115dup) variant causes a inframe insertion change. The variant allele was found at a frequency of 0.00196 in 1,478,304 control chromosomes in the GnomAD database, including 31 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0055 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (30 hom.)
• Consequence: PALLD ENST00000507735.6 inframe_insertion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 7.07

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 ENST00000507735.6. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 4-168878227-G-GCCA is Benign according to our data. Variant chr4-168878227-G-GCCA is described in ClinVar as [Benign]. Clinvar id is 476388.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00547 (798/145980) while in subpopulation SAS AF= 0.022 (96/4370). AF 95% confidence interval is 0.0184. There are 1 homozygotes in gnomad4. There are 398 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 798 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PALLD	NM_001166108.2	c.1965-12689_1965-12687dup		intron_variant		ENST00000505667.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PALLD	ENST00000505667.6	c.1965-12689_1965-12687dup		intron_variant		1	NM_001166108.2	A2

Frequencies

GnomAD3 genomes AF: 0.00545 AC: 795 AN: 145908 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0162

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00274

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0219

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00329

Gnomad NFE AF: 0.000283

Gnomad OTH AF: 0.00492

GnomAD3 exomes AF: 0.00398 AC: 446 AN: 112030 Hom.: 8 AF XY: 0.00504 AC XY: 312 AN XY: 61874

Gnomad AFR exome AF: 0.0150

Gnomad AMR exome AF: 0.00144

Gnomad ASJ exome AF: 0.000537

Gnomad EAS exome AF: 0.000244

Gnomad SAS exome AF: 0.0171

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000715

Gnomad OTH exome AF: 0.00321

GnomAD4 exome AF: 0.00158 AC: 2100 AN: 1332324 Hom.: 30 Cov.: 46 AF XY: 0.00203 AC XY: 1332 AN XY: 657616

Gnomad4 AFR exome AF: 0.0166

Gnomad4 AMR exome AF: 0.00152

Gnomad4 ASJ exome AF: 0.000393

Gnomad4 EAS exome AF: 0.000129

Gnomad4 SAS exome AF: 0.0167

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000121

Gnomad4 OTH exome AF: 0.00294

GnomAD4 genome AF: 0.00547 AC: 798 AN: 145980 Hom.: 1 Cov.: 32 AF XY: 0.00559 AC XY: 398 AN XY: 71232

Gnomad4 AFR AF: 0.0163

Gnomad4 AMR AF: 0.00274

Gnomad4 ASJ AF: 0.000289

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0220

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000283

Gnomad4 OTH AF: 0.00488

Alfa AF: 0.00246 Hom.: 0

Asia WGS AF: 0.00696 AC: 24 AN: 3462

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The PALLD p.Pro115dup variant was not identified in the literature nor was it identified in COSMIC. The variant was identified in dbSNP (ID: rs201979617) and ClinVar (classified as benign by Invitae). The variant was identified in control databases in 597 of 142532 chromosomes (8 homozygous) at a frequency of 0.004189 (Genome Aggregation Database March 6, 2019, v2.1.1). This variant is an in-frame insertion resulting in the duplication of a proline (pro) residue at codon 115; the impact of this alteration on PALLD protein function is not known. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. -

Pancreatic adenocarcinoma Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 27, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

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: rs201979617; hg19: chr4-169799378;