rs864622316

Variant names:

• chr4-168903804-C-A
• rs864622316
• NM_001166108.2:c.2520C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The ENST00000505667.6(PALLD):​c.2520C>A​(p.His840Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H840D) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PALLD ENST00000505667.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 6.18
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000505667.6. 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.2520C>A	p.His840Gln	missense	Exon 15 of 22	NP_001159580.1
	PALLD	NM_016081.4		c.2469C>A	p.His823Gln	missense	Exon 14 of 21	NP_057165.3
	PALLD	NM_001166109.2		c.1323C>A	p.His441Gln	missense	Exon 13 of 19	NP_001159581.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PALLD	ENST00000505667.6	TSL:1 MANE Select	c.2520C>A	p.His840Gln	missense	Exon 15 of 22	ENSP00000425556.1
	PALLD	ENST00000261509.10	TSL:1	c.2469C>A	p.His823Gln	missense	Exon 14 of 21	ENSP00000261509.6
	PALLD	ENST00000507735.6	TSL:1	c.1008C>A	p.His336Gln	missense	Exon 6 of 12	ENSP00000424016.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.098	T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.063	D
MetaRNN	Uncertain	0.70	D
MetaSVM	Benign	-0.37	T
PhyloP100		6.2
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Uncertain	0.36
Sift	Uncertain	0.021	D
Sift4G	Uncertain	0.057	T
Vest4		0.82
MVP		0.69
MPC		0.78
ClinPred		0.99	D
GERP RS		5.4
gMVP		0.60
Mutation Taster		=30/70	disease causing

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: rs864622316; hg19: chr4-169824955;