rs864622226

Positions:

• chr4-168878186-A-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The ENST00000507735.6(PALLD):​c.295A>C​(p.Thr99Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T99K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000089 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0000085 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PALLD ENST00000507735.6 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.937

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06601599).
• BP6: Variant 4-168878186-A-C is Benign according to our data. Variant chr4-168878186-A-C is described in ClinVar as [Benign]. Clinvar id is 219732.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PALLD	NM_001166108.2	c.1965-12736A>C		intron_variant		ENST00000505667.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PALLD	ENST00000505667.6	c.1965-12736A>C		intron_variant		1	NM_001166108.2	A2

Frequencies

GnomAD3 genomes AF: 0.00 AC: 9 AN: 101166 Hom.: 0 Cov.: 30 FAILED QC

Gnomad AFR AF: 0.000238

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000102

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000202

Gnomad OTH AF: 0.000732

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000851 AC: 10 AN: 1175768 Hom.: 0 Cov.: 44 AF XY: 0.00000691 AC XY: 4 AN XY: 578994

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000143

Gnomad4 FIN exome AF: 0.0000560

Gnomad4 NFE exome AF: 0.00000735

Gnomad4 OTH exome AF: 0.0000224

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000889 AC: 9 AN: 101188 Hom.: 0 Cov.: 30 AF XY: 0.0000407 AC XY: 2 AN XY: 49104

Gnomad4 AFR AF: 0.000238

Gnomad4 AMR AF: 0.000102

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000202

Gnomad4 OTH AF: 0.000727

Alfa AF: 0.0247 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Pancreatic adenocarcinoma Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Oct 30, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	3.4
DANN	Benign	0.48
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.066	T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.97	D;D;D;N;N
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.074
Sift	Benign	0.32	T
Sift4G	Benign	0.54	T
Vest4		0.10
MVP		0.11
ClinPred		0.045	T
GERP RS		-3.9

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: rs864622226; hg19: chr4-169799337; COSMIC: COSV105053435;