ENST00000507735.6:c.267G>C

Variant names:

• chr4-168878158-G-C
• rs863224384
• ENST00000507735.6:c.267G>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The ENST00000507735.6(PALLD):​c.267G>C​(p.Pro89Pro) 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 Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P89P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.012 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PALLD ENST00000507735.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.98
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 4-168878158-G-C is Benign according to our data. Variant chr4-168878158-G-C is described in ClinVar as Benign. ClinVar VariationId is 215804.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.98 with no splicing effect.

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.1965-12764G>C		intron	N/A	NP_001159580.1
	PALLD	NM_001166110.2		c.267G>C	p.Pro89Pro	synonymous	Exon 2 of 12	NP_001159582.1
	PALLD	NM_016081.4		c.1965-12764G>C		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.267G>C	p.Pro89Pro	synonymous	Exon 2 of 12	ENSP00000424016.1
	PALLD	ENST00000505667.6	TSL:1 MANE Select	c.1965-12764G>C		intron	N/A	ENSP00000425556.1
	PALLD	ENST00000261509.10	TSL:1	c.1965-12764G>C		intron	N/A	ENSP00000261509.6

Frequencies

GnomAD3 genomes AF: 0.00142 AC: 183 AN: 129164 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00271

Gnomad AMI AF: 0.00133

Gnomad AMR AF: 0.000837

Gnomad ASJ AF: 0.000311

Gnomad EAS AF: 0.00179

Gnomad SAS AF: 0.00308

Gnomad FIN AF: 0.00403

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.00168

GnomAD2 exomes AF: 0.0161 AC: 1152 AN: 71534 AF XY: 0.0128

Gnomad AFR exome AF: 0.0627

Gnomad AMR exome AF: 0.0513

Gnomad ASJ exome AF: 0.0143

Gnomad EAS exome AF: 0.0169

Gnomad FIN exome AF: 0.00958

Gnomad NFE exome AF: 0.00922

Gnomad OTH exome AF: 0.0172

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0115 AC: 7237 AN: 629276 Hom.: 0 Cov.: 30 AF XY: 0.0107 AC XY: 3385 AN XY: 315000

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0217 AC: 243 AN: 11194

American (AMR) AF: 0.0525 AC: 709 AN: 13508

Ashkenazi Jewish (ASJ) AF: 0.0127 AC: 136 AN: 10668

East Asian (EAS) AF: 0.00896 AC: 55 AN: 6138

South Asian (SAS) AF: 0.00674 AC: 360 AN: 53404

European-Finnish (FIN) AF: 0.00966 AC: 100 AN: 10356

Middle Eastern (MID) AF: 0.0165 AC: 29 AN: 1756

European-Non Finnish (NFE) AF: 0.0106 AC: 5295 AN: 498798

Other (OTH) AF: 0.0132 AC: 310 AN: 23454

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00140 AC: 181 AN: 129240 Hom.: 0 Cov.: 32 AF XY: 0.00130 AC XY: 82 AN XY: 62876

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00271 AC: 91 AN: 33574

American (AMR) AF: 0.000835 AC: 11 AN: 13174

Ashkenazi Jewish (ASJ) AF: 0.000311 AC: 1 AN: 3218

East Asian (EAS) AF: 0.00179 AC: 7 AN: 3910

South Asian (SAS) AF: 0.00279 AC: 10 AN: 3582

European-Finnish (FIN) AF: 0.00403 AC: 31 AN: 7690

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 266

European-Non Finnish (NFE) AF: 0.000424 AC: 26 AN: 61264

Other (OTH) AF: 0.00166 AC: 3 AN: 1808

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00816 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:1

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

Sep 10, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.87
DANN	Benign	0.59
PhyloP100		-3.0
Mutation Taster		=100/0	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: rs863224384; hg19: chr4-169799309; COSMIC: COSV107223711;