rs543821321

Variant names:

• chr4-168878286-G-A
• rs543821321
• ENST00000507735.6:c.395G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The ENST00000507735.6(PALLD):​c.395G>A​(p.Arg132His) variant causes a missense change. The variant allele was found at a frequency of 0.00128 in 1,526,406 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R132S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0015 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (5 hom.)
• Consequence: PALLD ENST00000507735.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.30
• Publications: 1 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: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007863641).
• BP6: Variant 4-168878286-G-A is Benign according to our data. Variant chr4-168878286-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136006.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 230 AD gene.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PALLD	NM_001166108.2	MANE Select	c.1965-12636G>A		intron	N/A	NP_001159580.1
	PALLD	NM_001166110.2		c.395G>A	p.Arg132His	missense	Exon 2 of 12	NP_001159582.1
	PALLD	NM_016081.4		c.1965-12636G>A		intron	N/A	NP_057165.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PALLD	ENST00000507735.6	TSL:1	c.395G>A	p.Arg132His	missense	Exon 2 of 12	ENSP00000424016.1
	PALLD	ENST00000505667.6	TSL:1 MANE Select	c.1965-12636G>A		intron	N/A	ENSP00000425556.1
	PALLD	ENST00000261509.10	TSL:1	c.1965-12636G>A		intron	N/A	ENSP00000261509.6

Frequencies

GnomAD3 genomes AF: 0.00151 AC: 230 AN: 151896 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000459

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00397

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00249

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00116 AC: 141 AN: 121558 AF XY: 0.00117

Gnomad AFR exome AF: 0.000201

Gnomad AMR exome AF: 0.000424

Gnomad ASJ exome AF: 0.000510

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00412

Gnomad NFE exome AF: 0.00155

Gnomad OTH exome AF: 0.00107

GnomAD4 exome AF: 0.00125 AC: 1722 AN: 1374400 Hom.: 5 Cov.: 46 AF XY: 0.00126 AC XY: 853 AN XY: 677982

African (AFR) AF: 0.000131 AC: 4 AN: 30542

American (AMR) AF: 0.000284 AC: 10 AN: 35164

Ashkenazi Jewish (ASJ) AF: 0.000442 AC: 11 AN: 24900

East Asian (EAS) AF: 0.00 AC: 0 AN: 34936

South Asian (SAS) AF: 0.00119 AC: 93 AN: 78142

European-Finnish (FIN) AF: 0.00383 AC: 128 AN: 33432

Middle Eastern (MID) AF: 0.000698 AC: 3 AN: 4296

European-Non Finnish (NFE) AF: 0.00132 AC: 1415 AN: 1075558

Other (OTH) AF: 0.00101 AC: 58 AN: 57430

GnomAD4 genome AF: 0.00151 AC: 230 AN: 152006 Hom.: 1 Cov.: 32 AF XY: 0.00141 AC XY: 105 AN XY: 74310

African (AFR) AF: 0.000169 AC: 7 AN: 41478

American (AMR) AF: 0.000458 AC: 7 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5124

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4812

European-Finnish (FIN) AF: 0.00397 AC: 42 AN: 10580

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00249 AC: 169 AN: 67946

Other (OTH) AF: 0.00142 AC: 3 AN: 2110

Alfa AF: 0.00302 Hom.: 0

Bravo AF: 0.000918

ExAC AF: 0.00117 AC: 21

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	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	-0.42	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	22
DANN	Uncertain	1.0
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.0079	T
MetaSVM	Benign	-0.97	T
PhyloP100		4.3
PROVEAN	Benign	-0.89	N
REVEL	Benign	0.080
Sift	Uncertain	0.025	D
Sift4G	Benign	0.076	T
Vest4		0.15
MVP		0.56
ClinPred		0.028	T
GERP RS		4.4
Mutation Taster		=96/4	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

Other links and lift over

dbSNP: rs543821321; hg19: chr4-169799437;