chr4-168878150-T-TCGCCCC

Variant names:

• chr4-168878150-T-TCGCCCC
• rs730882137
• ENST00000507735.6:c.270_275dupCCCGCC

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP3 BP6_Very_Strong

The NM_001166110.2(PALLD):​c.270_275dupCCCGCC​(p.Pro91_Pro92dup) variant causes a disruptive inframe insertion change. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P92P) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0082 (10 hom., cov: 32)
  • Exomes 𝑓: 0.00081 (13 hom.)
  • Failed GnomAD Quality Control
• Consequence: PALLD NM_001166110.2 disruptive_inframe_insertion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.82
• Publications: 0 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 -9 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001166110.2
• BP6: Variant 4-168878150-T-TCGCCCC is Benign according to our data. Variant chr4-168878150-T-TCGCCCC is described in ClinVar as Benign. ClinVar VariationId is 220482.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001166110.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PALLD	NM_001166108.2	MANE Select	c.1965-12761_1965-12756dupCCCGCC		intron	N/A	NP_001159580.1	Q8WX93-9
	PALLD	NM_001166110.2		c.270_275dupCCCGCC	p.Pro91_Pro92dup	disruptive_inframe_insertion	Exon 2 of 12	NP_001159582.1	Q8WX93-4
	PALLD	NM_016081.4		c.1965-12761_1965-12756dupCCCGCC		intron	N/A	NP_057165.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PALLD	ENST00000507735.6	TSL:1	c.270_275dupCCCGCC	p.Pro91_Pro92dup	disruptive_inframe_insertion	Exon 2 of 12	ENSP00000424016.1	Q8WX93-4
	PALLD	ENST00000505667.6	TSL:1 MANE Select	c.1965-12761_1965-12756dupCCCGCC		intron	N/A	ENSP00000425556.1	Q8WX93-9
	PALLD	ENST00000261509.10	TSL:1	c.1965-12761_1965-12756dupCCCGCC		intron	N/A	ENSP00000261509.6	Q8WX93-2

Frequencies

GnomAD3 genomes AF: 0.00820 AC: 1225 AN: 149428 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.0282

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00416

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000426

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00968

Gnomad NFE AF: 0.000208

Gnomad OTH AF: 0.00436

GnomAD2 exomes AF: 0.0000334 AC: 3 AN: 89912 AF XY: 0.0000198

Gnomad AFR exome AF: 0.000877

Gnomad AMR exome AF: 0.0000552

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000814 AC: 1088 AN: 1336966 Hom.: 13 Cov.: 30 AF XY: 0.000724 AC XY: 477 AN XY: 658994

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

African (AFR) AF: 0.0278 AC: 749 AN: 26934

American (AMR) AF: 0.000597 AC: 18 AN: 30164

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23600

East Asian (EAS) AF: 0.0000654 AC: 2 AN: 30602

South Asian (SAS) AF: 0.0000537 AC: 4 AN: 74530

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33152

Middle Eastern (MID) AF: 0.00224 AC: 9 AN: 4026

European-Non Finnish (NFE) AF: 0.000171 AC: 181 AN: 1058386

Other (OTH) AF: 0.00225 AC: 125 AN: 55572

⚠️ 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: 0.00820 AC: 1226 AN: 149536 Hom.: 10 Cov.: 32 AF XY: 0.00826 AC XY: 604 AN XY: 73108

African (AFR) AF: 0.0282 AC: 1135 AN: 40274

American (AMR) AF: 0.00416 AC: 63 AN: 15146

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3450

East Asian (EAS) AF: 0.00 AC: 0 AN: 5000

South Asian (SAS) AF: 0.000426 AC: 2 AN: 4690

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10402

Middle Eastern (MID) AF: 0.0104 AC: 3 AN: 288

European-Non Finnish (NFE) AF: 0.000208 AC: 14 AN: 67302

Other (OTH) AF: 0.00431 AC: 9 AN: 2086

Alfa AF: 0.0000787 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)
-	-	1	PALLD-related disorder (1)
-	-	1	Pancreatic adenocarcinoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.8
Mutation Taster		=80/20	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs730882137; hg19: chr4-169799301;