ENST00000507735.6:c.496A>C

Variant names:

• chr4-168878387-A-C
• rs878854266
• ENST00000507735.6:c.496A>C
• PALLD p.Thr166Pro

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000507735.6(PALLD):​c.496A>C​(p.Thr166Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 151,646 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/18 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. T166N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 7.5e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PALLD ENST00000507735.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.19
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.094516546).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000507735.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PALLD	NM_001166108.2	MANE Select	c.1965-12535A>C		intron	N/A	NP_001159580.1	Q8WX93-9
	PALLD	NM_001166110.2		c.496A>C	p.Thr166Pro	missense	Exon 2 of 12	NP_001159582.1	Q8WX93-4
	PALLD	NM_016081.4		c.1965-12535A>C		intron	N/A	NP_057165.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PALLD	ENST00000507735.6	TSL:1	c.496A>C	p.Thr166Pro	missense	Exon 2 of 12	ENSP00000424016.1	Q8WX93-4
	PALLD	ENST00000505667.6	TSL:1 MANE Select	c.1965-12535A>C		intron	N/A	ENSP00000425556.1	Q8WX93-9
	PALLD	ENST00000261509.10	TSL:1	c.1965-12535A>C		intron	N/A	ENSP00000261509.6	Q8WX93-2

Frequencies

GnomAD3 genomes AF: 0.0000198 AC: 3 AN: 151646 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000727

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 7.46e-7 AC: 1 AN: 1340906 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 659390

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 29022

American (AMR) AF: 0.00 AC: 0 AN: 29826

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23226

East Asian (EAS) AF: 0.00 AC: 0 AN: 33400

South Asian (SAS) AF: 0.00 AC: 0 AN: 73890

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32516

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3948

European-Non Finnish (NFE) AF: 9.44e-7 AC: 1 AN: 1059258

Other (OTH) AF: 0.00 AC: 0 AN: 55820

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000198 AC: 3 AN: 151646 Hom.: 0 Cov.: 32 AF XY: 0.0000270 AC XY: 2 AN XY: 74036

African (AFR) AF: 0.0000727 AC: 3 AN: 41240

American (AMR) AF: 0.00 AC: 0 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5148

South Asian (SAS) AF: 0.00 AC: 0 AN: 4804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10564

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67882

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)
-	1	-	Pancreatic adenocarcinoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	19
DANN	Benign	0.92
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.095	T
MetaSVM	Benign	-1.0	T
PhyloP100		3.2
PROVEAN	Benign	-0.35	N
REVEL	Benign	0.12
Sift	Benign	0.27	T
Sift4G	Benign	0.70	T
Mutation Taster		=81/19	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs878854266;

hg19: chr4-169799538;