rs368350042

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001166110.2(PALLD):c.466G>A(p.Val156Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00188 in 1,518,194 control chromosomes in the GnomAD database, including 66 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0011 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0020 ( 62 hom. )

Consequence

PALLD
NM_001166110.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 5.34

Variant links:

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]

PALLD links:

CBR4 (HGNC:):

CBR4 links:

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]

CBR4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0053824782).

BP6

Variant 4-168878357-G-A is Benign according to our data. Variant chr4-168878357-G-A is described in ClinVar as [Benign]. Clinvar id is 136009.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0011 (167/152272) while in subpopulation SAS AF= 0.0335 (162/4830). AF 95% confidence interval is 0.0293. There are 4 homozygotes in gnomad4. There are 125 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 167 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PALLD	NM_001166108.2 linkuse as main transcript	c.1965-12565G>A		intron_variant		ENST00000505667.6	NP_001159580.1	Q8WX93-9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PALLD	ENST00000505667.6 linkuse as main transcript	c.1965-12565G>A		intron_variant		1	NM_001166108.2	ENSP00000425556.1		Q8WX93-9

Frequencies

GnomAD3 genomes

AF:

0.00111

AC:

169

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0339

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00596

AC:

680

AN:

114074

Hom.:

AF XY:

0.00806

AC XY:

507

AN XY:

62926

show subpopulations

Gnomad AFR exome

AF:

0.000239

Gnomad AMR exome

AF:

0.000134

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000236

Gnomad OTH exome

AF:

0.00315

GnomAD4 exome

AF:

0.00197

AC:

2691

AN:

1365922

Hom.:

Cov.:

AF XY:

0.00286

AC XY:

1924

AN XY:

673486

show subpopulations

Gnomad4 AFR exome

AF:

0.000101

Gnomad4 AMR exome

AF:

0.000233

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0326

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000252

Gnomad4 OTH exome

AF:

0.00240

GnomAD4 genome

AF:

0.00110

AC:

167

AN:

152272

Hom.:

Cov.:

AF XY:

0.00168

AC XY:

125

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0335

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000386

Hom.:

Bravo

AF:

0.000310

ExAC

AF:

0.0149

AC:

230

Asia WGS

AF:

0.0180

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The PALLD p.Val156Ile variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs368350042) and ClinVar (classified as benign by Invitae). The variant was identified in control databases in 684 of 145410 chromosomes (13 homozygous) at a frequency of 0.004704 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: South Asian in 664 of 20284 chromosomes (freq: 0.03274), Other in 15 of 4572 chromosomes (freq: 0.003281), Latino in 3 of 23164 chromosomes (freq: 0.00013), African in 1 of 12862 chromosomes (freq: 0.000078) and European (non-Finnish) in 1 of 57790 chromosomes (freq: 0.000017), but was not observed in the Ashkenazi Jewish, East Asian, or European (Finnish) populations. The p.Val156 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 29, 2024	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Pancreatic cancer, susceptibility to, 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Pancreatic adenocarcinoma

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Uncertain

1.0

Eigen

Benign

0.060

Eigen_PC

Benign

0.18

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.81

MetaRNN

Benign

0.0054

MetaSVM

Benign

-0.98

PROVEAN

Benign

-0.48

REVEL

Benign

0.052

Sift

Benign

0.090

Sift4G

Benign

0.17

Vest4

0.12

ClinPred

0.015

GERP RS

4.8

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over