4-168894654-C-G

Variant names:

• chr4-168894654-C-G
• rs1553969553
• NM_001166108.2:c.2176C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001166108.2(PALLD):​c.2176C>G​(p.Pro726Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P726T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PALLD NM_001166108.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.49
• 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
• BP4: Computational evidence support a benign effect (MetaRNN=0.2783478).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PALLD	NM_001166108.2	c.2176C>G	p.Pro726Ala	missense_variant	Exon 12 of 22	ENST00000505667.6	NP_001159580.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PALLD	ENST00000505667.6	c.2176C>G	p.Pro726Ala	missense_variant	Exon 12 of 22	1	NM_001166108.2	ENSP00000425556.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Jan 31, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.P726A variant (also known as c.2176C>G), located in coding exon 11 of the PALLD gene, results from a C to G substitution at nucleotide position 2176. The proline at codon 726 is replaced by alanine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Pancreatic adenocarcinoma Uncertain:1

Jun 15, 2023

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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 1787184). 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 sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 239 of the PALLD protein (p.Pro239Ala). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.0045	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.055	.;.;.;.;T;.
Eigen	Benign	0.19
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.87	D;D;D;D;D;D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.28	T;T;T;T;T;T
MetaSVM	Benign	-0.70	T
PhyloP100		2.5
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-2.5	D;D;D;D;D;D
REVEL	Benign	0.15
Sift	Benign	0.11	T;D;T;D;D;T
Sift4G	Benign	0.13	T;T;T;D;T;T
Vest4		0.26
MVP		0.64
MPC		0.30
ClinPred		0.80	D
GERP RS		5.2
gMVP		0.23
Mutation Taster		=56/44	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1553969553; hg19: chr4-169815805;