chr4-168878297-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000507735.6(PALLD):c.406A>G(p.Ser136Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.613 in 1,525,872 control chromosomes in the GnomAD database, including 295,098 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S136R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.51 ( 22843 hom., cov: 33)

Exomes 𝑓: 0.62 ( 272255 hom. )

Consequence

PALLD
ENST00000507735.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.339

Publications

24 publications found

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: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 was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=3.1354703E-6).

BP6

Variant 4-168878297-A-G is Benign according to our data. Variant chr4-168878297-A-G is described in ClinVar as Benign. ClinVar VariationId is 182793.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.645 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PALLD	NM_001166108.2 link	c.1965-12625A>G		intron_variant	Intron 10 of 21	ENST00000505667.6	NP_001159580.1	Q8WX93-9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PALLD	ENST00000505667.6 link	c.1965-12625A>G		intron_variant	Intron 10 of 21	1	NM_001166108.2	ENSP00000425556.1		Q8WX93-9

Frequencies

GnomAD3 genomes

AF:

0.507

AC:

77069

AN:

151876

Hom.:

22832

Cov.:

show subpopulations

Gnomad AFR

AF:

0.177

Gnomad AMI

AF:

0.604

Gnomad AMR

AF:

0.554

Gnomad ASJ

AF:

0.612

Gnomad EAS

AF:

0.536

Gnomad SAS

AF:

0.663

Gnomad FIN

AF:

0.730

Gnomad MID

AF:

0.532

Gnomad NFE

AF:

0.643

Gnomad OTH

AF:

0.525

GnomAD2 exomes

AF:

0.613

AC:

74166

AN:

121080

AF XY:

0.618

show subpopulations

Gnomad AFR exome

AF:

0.136

Gnomad AMR exome

AF:

0.626

Gnomad ASJ exome

AF:

0.621

Gnomad EAS exome

AF:

0.523

Gnomad FIN exome

AF:

0.734

Gnomad NFE exome

AF:

0.640

Gnomad OTH exome

AF:

0.602

GnomAD4 exome

AF:

0.624

AC:

857519

AN:

1373882

Hom.:

272255

Cov.:

AF XY:

0.627

AC XY:

424889

AN XY:

677634

show subpopulations

African (AFR)

AF:

0.152

AC:

4672

AN:

30638

American (AMR)

AF:

0.620

AC:

21747

AN:

35078

Ashkenazi Jewish (ASJ)

AF:

0.617

AC:

15336

AN:

24868

East Asian (EAS)

AF:

0.535

AC:

18668

AN:

34880

South Asian (SAS)

AF:

0.664

AC:

51877

AN:

78108

European-Finnish (FIN)

AF:

0.730

AC:

24399

AN:

33422

Middle Eastern (MID)

AF:

0.568

AC:

2408

AN:

4240

European-Non Finnish (NFE)

AF:

0.636

AC:

684299

AN:

1075288

Other (OTH)

AF:

0.595

AC:

34113

AN:

57360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

17703

35406

53108

70811

88514

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18186

36372

54558

72744

90930

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.507

AC:

77091

AN:

151990

Hom.:

22843

Cov.:

AF XY:

0.515

AC XY:

38272

AN XY:

74310

show subpopulations

African (AFR)

AF:

0.176

AC:

7317

AN:

41486

American (AMR)

AF:

0.554

AC:

8466

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.612

AC:

2125

AN:

3470

East Asian (EAS)

AF:

0.536

AC:

2740

AN:

5108

South Asian (SAS)

AF:

0.664

AC:

3201

AN:

4818

European-Finnish (FIN)

AF:

0.730

AC:

7723

AN:

10582

Middle Eastern (MID)

AF:

0.538

AC:

157

AN:

292

European-Non Finnish (NFE)

AF:

0.643

AC:

43700

AN:

67924

Other (OTH)

AF:

0.527

AC:

1114

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1685

3370

5054

6739

8424

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

674

1348

2022

2696

3370

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.579

Hom.:

10814

Bravo

AF:

0.479

TwinsUK

AF:

0.656

AC:

2431

ALSPAC

AF:

0.631

AC:

2433

ExAC

AF:

0.540

AC:

8133

Asia WGS

AF:

0.622

AC:

2160

AN:

3472

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Jul 30, 2020

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as 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. -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Pancreatic cancer, susceptibility to, 1

Benign:1

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Pancreatic adenocarcinoma

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.63

CADD

Benign

1.9

(source)

DANN

Benign

0.75

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.039

LIST_S2

Benign

0.34

MetaRNN

Benign

0.0000031

MetaSVM

Benign

-0.96

PhyloP100

-0.34

PROVEAN

Benign

-0.94

REVEL

Benign

0.094

Sift

Benign

0.75

Sift4G

Benign

0.37

Vest4

0.015

ClinPred

0.0034

GERP RS

-5.0

Mutation Taster

=95/5

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over