rs1136603

Variant names:

• chr4-168928086-G-A
• rs1136603
• NM_001166108.2:c.*1906G>A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001166108.2(PALLD):​c.*1906G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.125 in 195,530 control chromosomes in the GnomAD database, including 1,670 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1384 hom., cov: 33)
  • Exomes 𝑓: 0.11 (286 hom.)
• Consequence: PALLD NM_001166108.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.95

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

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 4-168928086-G-A is Benign according to our data. Variant chr4-168928086-G-A is described in ClinVar as [Benign]. Clinvar id is 348067.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.179 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PALLD	NM_001166108.2	c.*1906G>A		3_prime_UTR_variant	Exon 22 of 22	ENST00000505667.6	NP_001159580.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PALLD	ENST00000505667.6	c.*1906G>A		3_prime_UTR_variant	Exon 22 of 22	1	NM_001166108.2	ENSP00000425556.1

Frequencies

GnomAD3 genomes AF: 0.128 AC: 19456 AN: 152022 Hom.: 1384 Cov.: 33

Gnomad AFR AF: 0.182

Gnomad AMI AF: 0.223

Gnomad AMR AF: 0.0912

Gnomad ASJ AF: 0.0965

Gnomad EAS AF: 0.0728

Gnomad SAS AF: 0.0789

Gnomad FIN AF: 0.0757

Gnomad MID AF: 0.209

Gnomad NFE AF: 0.119

Gnomad OTH AF: 0.133

GnomAD4 exome AF: 0.114 AC: 4926 AN: 43390 Hom.: 286 Cov.: 0 AF XY: 0.115 AC XY: 2309 AN XY: 20092

Gnomad4 AFR exome AF: 0.183

Gnomad4 AMR exome AF: 0.0861

Gnomad4 ASJ exome AF: 0.0938

Gnomad4 EAS exome AF: 0.0738

Gnomad4 SAS exome AF: 0.0513

Gnomad4 FIN exome AF: 0.0852

Gnomad4 NFE exome AF: 0.125

Gnomad4 OTH exome AF: 0.109

GnomAD4 genome AF: 0.128 AC: 19472 AN: 152140 Hom.: 1384 Cov.: 33 AF XY: 0.124 AC XY: 9226 AN XY: 74378

Gnomad4 AFR AF: 0.182

Gnomad4 AMR AF: 0.0911

Gnomad4 ASJ AF: 0.0965

Gnomad4 EAS AF: 0.0729

Gnomad4 SAS AF: 0.0779

Gnomad4 FIN AF: 0.0757

Gnomad4 NFE AF: 0.119

Gnomad4 OTH AF: 0.132

Alfa AF: 0.119 Hom.: 832

Bravo AF: 0.132

Asia WGS AF: 0.0770 AC: 267 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Pancreatic cancer, susceptibility to, 1 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	7.5
DANN	Benign	0.68

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

LitVar

Other links and lift over

dbSNP: rs1136603; hg19: chr4-169849237; COSMIC: COSV54993143; COSMIC: COSV54993143;