4-168913991-G-C

Variant names:

• chr4-168913991-G-C
• NM_001166108.2:c.2687G>C

Variant summary

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

The NM_001166108.2(PALLD):​c.2687G>C​(p.Arg896Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. R896Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PALLD NM_001166108.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.39

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PALLD	NM_001166108.2	c.2687G>C	p.Arg896Pro	missense_variant	Exon 16 of 22	ENST00000505667.6	NP_001159580.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PALLD	ENST00000505667.6	c.2687G>C	p.Arg896Pro	missense_variant	Exon 16 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:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 02, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R879P variant (also known as c.2636G>C), located in coding exon 14 of the PALLD gene, results from a G to C substitution at nucleotide position 2636. The arginine at codon 879 is replaced by proline, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.063	T
BayesDel_noAF	Benign	-0.15
CADD	Pathogenic	28
DANN	Uncertain	1.0
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Benign	0.054	D
MetaRNN	Uncertain	0.52	D;D;D;D
MetaSVM	Benign	-0.57	T
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.8	N;N;N;N
REVEL	Benign	0.17
Sift	Benign	0.098	T;T;T;T
Sift4G	Benign	0.22	T;T;T;T
Vest4		0.49
MVP		0.70
MPC		0.92
ClinPred		0.95	D
GERP RS		5.5
gMVP		0.45

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-169835142;