rs1060502974

chr4-168878094-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000507735.6(PALLD):c.203C>T(p.Pro68Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000387 in 1,292,642 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000039 (0 hom.)
• Consequence: PALLD ENST00000507735.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.13

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19031054).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PALLD	NM_001166108.2	c.1965-12828C>T		intron_variant		ENST00000505667.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PALLD	ENST00000505667.6	c.1965-12828C>T		intron_variant		1	NM_001166108.2	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000387 AC: 5 AN: 1292642 Hom.: 0 Cov.: 31 AF XY: 0.00000315 AC XY: 2 AN XY: 635426

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000385

Gnomad4 OTH exome AF: 0.0000186

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Pancreatic adenocarcinoma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Apr 07, 2019

In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65"). While this variant is not present in population databases (no rsID), the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in an individual with a PALLD-related disease. This sequence change replaces proline with leucine at codon 68 of the PALLD protein (p.Pro68Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.069	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	17
Dann	Uncertain	0.99
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.33
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.080	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;D;D;D
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.18
Sift	Benign	0.035	D
Sift4G	Benign	0.072	T
Vest4		0.16
MVP		0.41
ClinPred		0.74	D
GERP RS		1.9

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: rs1060502974; hg19: chr4-169799245;