rs368350042

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

2
12

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]
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]

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
PALLDNM_001166108.2 linkuse as main transcriptc.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
PALLDENST00000505667.6 linkuse as main transcriptc.1965-12565G>A intron_variant 1 NM_001166108.2 ENSP00000425556.1 Q8WX93-9

Frequencies

GnomAD3 genomes
AF:
0.00111
AC:
169
AN:
152154
Hom.:
4
Cov.:
32
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.:
13
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.:
62
Cov.:
35
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.:
4
Cov.:
32
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.:
0
Bravo
AF:
0.000310
ExAC
AF:
0.0149
AC:
230
Asia WGS
AF:
0.0180
AC:
61
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 providedclinical testingDepartment 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 submitterclinical testingAmbry GeneticsJul 29, 2024This 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 submitterclinical testingKCCC/NGS Laboratory, Kuwait Cancer Control CenterJul 07, 2023- -
Pancreatic adenocarcinoma Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 30, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
-0.44
T
BayesDel_noAF
Benign
-0.37
CADD
Benign
22
DANN
Uncertain
1.0
Eigen
Benign
0.060
Eigen_PC
Benign
0.18
FATHMM_MKL
Uncertain
0.86
D
LIST_S2
Benign
0.81
T
MetaRNN
Benign
0.0054
T
MetaSVM
Benign
-0.98
T
PROVEAN
Benign
-0.48
N
REVEL
Benign
0.052
Sift
Benign
0.090
T
Sift4G
Benign
0.17
T
Vest4
0.12
ClinPred
0.015
T
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.

Other links and lift over

dbSNP: rs368350042; hg19: chr4-169799508; API