chr4-168877902-T-G

Position:

• chr4-168877902-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000507735.6(PALLD):​c.11T>G​(p.Leu4Arg) 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. 11/15 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. L4P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PALLD ENST00000507735.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.27

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3967299).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PALLD	NM_001166108.2	c.1965-13020T>G		intron_variant		ENST00000505667.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PALLD	ENST00000505667.6	c.1965-13020T>G		intron_variant		1	NM_001166108.2	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 10, 2021

The p.L4R variant (also known as c.11T>G), located in coding exon 1 of the PALLD gene, results from a T to G substitution at nucleotide position 11. The leucine at codon 4 is replaced by arginine, an amino acid with dissimilar 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	0.0098	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	19
DANN	Uncertain	1.0
Eigen	Benign	0.0073
Eigen_PC	Benign	0.027
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.52	T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.40	T
MetaSVM	Benign	-0.83	T
MutationTaster	Benign	0.86	D;D;D;D;D
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.10
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.012	D
Vest4		0.44
MutPred		0.42		Gain of MoRF binding (P = 0.0011);
MVP		0.55
ClinPred		0.85	D
GERP RS		4.8

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: chr4-169799053;