4-168878164-G-C

Variant names:

• chr4-168878164-G-C
• rs777359545
• ENST00000507735.6:c.273G>C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_001166110.2(PALLD):​c.273G>C​(p.Pro91Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 30)
  • Exomes 𝑓: 0.028 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PALLD NM_001166110.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.600

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 4-168878164-G-C is Benign according to our data. Variant chr4-168878164-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 215805.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-168878164-G-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.6 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PALLD	NM_001166108.2	c.1965-12758G>C		intron_variant	Intron 10 of 21	ENST00000505667.6	NP_001159580.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PALLD	ENST00000505667.6	c.1965-12758G>C		intron_variant	Intron 10 of 21	1	NM_001166108.2	ENSP00000425556.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 161 AN: 102898 Hom.: 0 Cov.: 30 FAILED QC

Gnomad AFR AF: 0.00299

Gnomad AMI AF: 0.00179

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.000379

Gnomad EAS AF: 0.00175

Gnomad SAS AF: 0.00171

Gnomad FIN AF: 0.00415

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000644

Gnomad OTH AF: 0.00147

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0280 AC: 10284 AN: 367294 Hom.: 0 Cov.: 25 AF XY: 0.0270 AC XY: 4998 AN XY: 185078

Gnomad4 AFR exome AF: 0.0451

Gnomad4 AMR exome AF: 0.131

Gnomad4 ASJ exome AF: 0.0401

Gnomad4 EAS exome AF: 0.0274

Gnomad4 SAS exome AF: 0.0277

Gnomad4 FIN exome AF: 0.0486

Gnomad4 NFE exome AF: 0.0235

Gnomad4 OTH exome AF: 0.0359

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00155 AC: 160 AN: 102930 Hom.: 0 Cov.: 30 AF XY: 0.00139 AC XY: 70 AN XY: 50308

Gnomad4 AFR AF: 0.00299

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.000379

Gnomad4 EAS AF: 0.00175

Gnomad4 SAS AF: 0.00171

Gnomad4 FIN AF: 0.00415

Gnomad4 NFE AF: 0.000624

Gnomad4 OTH AF: 0.00146

Alfa AF: 0.0102 Hom.: 0

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 29, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This 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. -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Pancreatic adenocarcinoma Benign:1

May 07, 2024

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
BayesDel_noAF	Benign	-0.64
CADD	Benign	7.1
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: rs777359545; hg19: chr4-169799315;