rs587780757

Variant names:

• chr4-168878082-C-G
• rs587780757
• ENST00000507735.6:c.191C>G

Your query was ambiguous. Multiple possible variants found:

• chr4-168878082-C-G
• chr4-168878082-C-T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001166110.2(PALLD):​c.191C>G​(p.Ala64Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000117 in 1,448,004 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A64T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: PALLD NM_001166110.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 0.826
• 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.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004498929).
• BP6: Variant 4-168878082-C-G is Benign according to our data. Variant chr4-168878082-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 136001.
• BS2: High AC in GnomAd4 at 28 AD gene.

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.1965-12840C>G		intron	N/A	NP_001159580.1
	PALLD	NM_001166110.2		c.191C>G	p.Ala64Gly	missense	Exon 2 of 12	NP_001159582.1
	PALLD	NM_016081.4		c.1965-12840C>G		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.191C>G	p.Ala64Gly	missense	Exon 2 of 12	ENSP00000424016.1
	PALLD	ENST00000505667.6	TSL:1 MANE Select	c.1965-12840C>G		intron	N/A	ENSP00000425556.1
	PALLD	ENST00000261509.10	TSL:1	c.1965-12840C>G		intron	N/A	ENSP00000261509.6

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 151864 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000589

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000440 AC: 25 AN: 56868 AF XY: 0.000460

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000178

Gnomad ASJ exome AF: 0.00448

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000233

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000110 AC: 142 AN: 1296140 Hom.: 0 Cov.: 31 AF XY: 0.000132 AC XY: 84 AN XY: 637334

African (AFR) AF: 0.000765 AC: 20 AN: 26148

American (AMR) AF: 0.0000898 AC: 2 AN: 22284

Ashkenazi Jewish (ASJ) AF: 0.00326 AC: 68 AN: 20842

East Asian (EAS) AF: 0.00 AC: 0 AN: 28696

South Asian (SAS) AF: 0.00 AC: 0 AN: 66872

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32340

Middle Eastern (MID) AF: 0.000916 AC: 4 AN: 4366

European-Non Finnish (NFE) AF: 0.0000231 AC: 24 AN: 1040824

Other (OTH) AF: 0.000446 AC: 24 AN: 53768

GnomAD4 genome AF: 0.000184 AC: 28 AN: 151864 Hom.: 0 Cov.: 32 AF XY: 0.000135 AC XY: 10 AN XY: 74192

African (AFR) AF: 0.0000725 AC: 3 AN: 41382

American (AMR) AF: 0.0000655 AC: 1 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.00576 AC: 20 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10518

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000589 AC: 4 AN: 67922

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.000181

ExAC AF: 0.000353 AC: 6

Asia WGS AF: 0.000584 AC: 2 AN: 3436

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Pancreatic cancer, susceptibility to, 1 (2)
-	-	1	not specified (1)
-	-	1	PALLD-related disorder (1)
-	-	1	Pancreatic adenocarcinoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	12
DANN	Benign	0.64
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.62	T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.0045	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.83
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.073
Sift	Benign	0.20	T
Sift4G	Benign	0.24	T
Vest4		0.053
MVP		0.35
ClinPred		0.017	T
GERP RS		2.7
Mutation Taster		=77/23	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: rs587780757; hg19: chr4-169799233;