rs864622087

Variant names:

• chr4-168878161-CCCGCCA-C
• rs864622087
• ENST00000507735.6:c.273_278delGCCACC

Your query was ambiguous. Multiple possible variants found:

• chr4-168878161-CCCGCCA-C
• chr4-168878161-CCCGCCA-CCCGCCACCGCCA

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP3

The ENST00000507735.6(PALLD):​c.273_278delGCCACC​(p.Pro92_Pro93del) variant causes a disruptive inframe deletion change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. P91P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0000015 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PALLD ENST00000507735.6 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.05
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP3: Nonframeshift variant in repetitive region in ENST00000507735.6

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000507735.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PALLD	NM_001166108.2	MANE Select	c.1965-12758_1965-12753delGCCACC		intron	N/A	NP_001159580.1
	PALLD	NM_001166110.2		c.273_278delGCCACC	p.Pro92_Pro93del	disruptive_inframe_deletion	Exon 2 of 12	NP_001159582.1
	PALLD	NM_016081.4		c.1965-12758_1965-12753delGCCACC		intron	N/A	NP_057165.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PALLD	ENST00000507735.6	TSL:1	c.273_278delGCCACC	p.Pro92_Pro93del	disruptive_inframe_deletion	Exon 2 of 12	ENSP00000424016.1
	PALLD	ENST00000505667.6	TSL:1 MANE Select	c.1965-12758_1965-12753delGCCACC		intron	N/A	ENSP00000425556.1
	PALLD	ENST00000261509.10	TSL:1	c.1965-12758_1965-12753delGCCACC		intron	N/A	ENSP00000261509.6

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000149 AC: 2 AN: 1339820 Hom.: 0 AF XY: 0.00000151 AC XY: 1 AN XY: 660412

African (AFR) AF: 0.00 AC: 0 AN: 27192

American (AMR) AF: 0.00 AC: 0 AN: 30558

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23756

East Asian (EAS) AF: 0.00 AC: 0 AN: 30872

South Asian (SAS) AF: 0.00 AC: 0 AN: 74818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33196

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4054

European-Non Finnish (NFE) AF: 0.00000189 AC: 2 AN: 1059664

Other (OTH) AF: 0.00 AC: 0 AN: 55710

GnomAD4 genome Cov.: 29

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Dec 16, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.273_278delGCCACC variant (also known as p.P93_P94del) is located in coding exon 1 of the PALLD gene. This variant results from an in-frame GCCACC deletion at nucleotide positions 273 to 278. This results in the in-frame deletion of two amino acids (PP) at codons 93 to 94. These amino acid positions are well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). The evidence for this gene-disease relationship is limited; therefore, the clinical significance of this alteration is unclear.

Pancreatic adenocarcinoma Uncertain:1

Jun 16, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 999237). This variant has not been reported in the literature in individuals affected with PALLD-related conditions. This variant is not present in population databases (gnomAD no frequency). This variant, c.273_278del, results in the deletion of 2 amino acid(s) of the PALLD protein (p.Pro93_Pro94del), but otherwise preserves the integrity of the reading frame.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.1
Mutation Taster		=114/86	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs864622087; hg19: chr4-169799312;