ENST00000507735.6:c.415C>T

Variant names:

• chr4-168878306-C-T
• rs121908291
• ENST00000507735.6:c.415C>T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4 BP6 BS2

The ENST00000507735.6(PALLD):​c.415C>T​(p.Pro139Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0008 in 1,527,100 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00086 (4 hom.)
• Consequence: PALLD ENST00000507735.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2 O:1
• Conservation: PhyloP100: 5.40

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.34723958).
• BP6: Variant 4-168878306-C-T is Benign according to our data. Variant chr4-168878306-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2572.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=2}.
• BS2: High AC in GnomAd4 at 37 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PALLD	NM_001166108.2	c.1965-12616C>T		intron_variant	Intron 10 of 21	ENST00000505667.6	NP_001159580.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PALLD	ENST00000505667.6	c.1965-12616C>T		intron_variant	Intron 10 of 21	1	NM_001166108.2	ENSP00000425556.1

Frequencies

GnomAD3 genomes AF: 0.000243 AC: 37 AN: 152194 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000470

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000205 AC: 25 AN: 122174 Hom.: 1 AF XY: 0.000239 AC XY: 16 AN XY: 67048

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000467

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000486

Gnomad OTH exome AF: 0.000531

GnomAD4 exome AF: 0.000862 AC: 1185 AN: 1374906 Hom.: 4 Cov.: 35 AF XY: 0.000843 AC XY: 572 AN XY: 678180

Gnomad4 AFR exome AF: 0.000163

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000512

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00107

Gnomad4 OTH exome AF: 0.000435

GnomAD4 genome AF: 0.000243 AC: 37 AN: 152194 Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10 AN XY: 74352

Gnomad4 AFR AF: 0.0000965

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000470

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000299 Hom.: 0

Bravo AF: 0.000249

ExAC AF: 0.0000607 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:1

Feb 06, 2014

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Oct 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.415C>T (p.P139S) alteration is located in exon 2 (coding exon 1) of the PALLD gene. This alteration results from a C to T substitution at nucleotide position 415, causing the proline (P) at amino acid position 139 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Pancreatic adenocarcinoma Uncertain:1

Jan 16, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 139 of the PALLD protein (p.Pro139Ser). This variant is present in population databases (rs121908291, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of PALLD-related conditions (PMID: 10454945, 11474289, 17194196, 17415588). It has also been observed to segregate with disease in related individuals. This variant is also known as 715C>T (Pro239Ser). ClinVar contains an entry for this variant (Variation ID: 2572). 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 disruptive. Experimental studies have shown that this missense change affects PALLD function (PMID: 17194196). 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. -

PALLD-related disorder Benign:1

Feb 26, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Pancreatic cancer, susceptibility to, 1 Other:1

Jun 01, 2007

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.090	T
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	20
DANN	Uncertain	1.0
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.77	T
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.35	T
MetaSVM	Uncertain	0.53	D
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.45
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.012	D
Vest4		0.38
MVP		0.70
ClinPred		0.21	T
GERP RS		4.6

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: rs121908291; hg19: chr4-169799457;