rs864622226

Variant names:

• chr4-168878186-A-C
• rs864622226
• ENST00000507735.6:c.295A>C

Variant summary

Our verdict is Likely benign. The variant received -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. 15/18 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. T99R) has been classified as Likely benign.

• 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
• 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: Likely_benign. The variant received -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 VariationId is 219732.Status of the report is criteria_provided_single_submitter, 1 stars.

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.1965-12736A>C		intron	N/A	NP_001159580.1
	PALLD	NM_001166110.2		c.295A>C	p.Thr99Pro	missense	Exon 2 of 12	NP_001159582.1
	PALLD	NM_016081.4		c.1965-12736A>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.295A>C	p.Thr99Pro	missense	Exon 2 of 12	ENSP00000424016.1
	PALLD	ENST00000505667.6	TSL:1 MANE Select	c.1965-12736A>C		intron	N/A	ENSP00000425556.1
	PALLD	ENST00000261509.10	TSL:1	c.1965-12736A>C		intron	N/A	ENSP00000261509.6

Frequencies

GnomAD3 genomes AF: 0.0000890 AC: 9 AN: 101166 Hom.: 0 Cov.: 30

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

GnomAD2 exomes AF: 0.00 AC: 0 AN: 100300 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00000851 AC: 10 AN: 1175768 Hom.: 0 Cov.: 44 AF XY: 0.00000691 AC XY: 4 AN XY: 578994

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

African (AFR) AF: 0.00 AC: 0 AN: 23078

American (AMR) AF: 0.00 AC: 0 AN: 26654

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17798

East Asian (EAS) AF: 0.00 AC: 0 AN: 19738

South Asian (SAS) AF: 0.0000143 AC: 1 AN: 70050

European-Finnish (FIN) AF: 0.0000560 AC: 1 AN: 17842

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3226

European-Non Finnish (NFE) AF: 0.00000735 AC: 7 AN: 952698

Other (OTH) AF: 0.0000224 AC: 1 AN: 44684

⚠️ 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: 0.0000889 AC: 9 AN: 101188 Hom.: 0 Cov.: 30 AF XY: 0.0000407 AC XY: 2 AN XY: 49104

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

African (AFR) AF: 0.000238 AC: 6 AN: 25230

American (AMR) AF: 0.000102 AC: 1 AN: 9836

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2708

East Asian (EAS) AF: 0.00 AC: 0 AN: 3428

South Asian (SAS) AF: 0.00 AC: 0 AN: 2818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5460

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.0000202 AC: 1 AN: 49542

Other (OTH) AF: 0.000727 AC: 1 AN: 1376

⚠️ 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: 0.0247 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Pancreatic adenocarcinoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
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
PhyloP100		0.94
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
Mutation Taster		=89/11	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: rs864622226; hg19: chr4-169799337; COSMIC: COSV105053435;