rs59633770

Variant names:

• chr4-168924976-C-T
• rs59633770
• NM_001166108.2:c.3256C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_001166108.2(PALLD):​c.3256C>T​(p.Leu1086Leu) variant causes a synonymous change. The variant allele was found at a frequency of 0.0011 in 1,614,110 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L1086L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (16 hom.)
• Consequence: PALLD NM_001166108.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 4.92
• Publications: 3 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.093).
• BP6: Variant 4-168924976-C-T is Benign according to our data. Variant chr4-168924976-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 182794.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00136 (207/152290) while in subpopulation EAS AF = 0.0231 (120/5186). AF 95% confidence interval is 0.0198. There are 1 homozygotes in GnomAd4. There are 121 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 207 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001166108.2. 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.3256C>T	p.Leu1086Leu	synonymous	Exon 20 of 22	NP_001159580.1
	PALLD	NM_016081.4		c.3205C>T	p.Leu1069Leu	synonymous	Exon 19 of 21	NP_057165.3
	PALLD	NM_001166109.2		c.2059C>T	p.Leu687Leu	synonymous	Exon 18 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.3256C>T	p.Leu1086Leu	synonymous	Exon 20 of 22	ENSP00000425556.1
	PALLD	ENST00000261509.10	TSL:1	c.3205C>T	p.Leu1069Leu	synonymous	Exon 19 of 21	ENSP00000261509.6
	PALLD	ENST00000507735.6	TSL:1	c.1744C>T	p.Leu582Leu	synonymous	Exon 11 of 12	ENSP00000424016.1

Frequencies

GnomAD3 genomes AF: 0.00136 AC: 207 AN: 152172 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0231

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00623

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.00211 AC: 531 AN: 251098 AF XY: 0.00206

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0172

Gnomad FIN exome AF: 0.00679

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00107 AC: 1571 AN: 1461820 Hom.: 16 Cov.: 32 AF XY: 0.00107 AC XY: 779 AN XY: 727230

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.0000671 AC: 3 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0253 AC: 1003 AN: 39688

South Asian (SAS) AF: 0.00125 AC: 108 AN: 86258

European-Finnish (FIN) AF: 0.00635 AC: 339 AN: 53414

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.0000576 AC: 64 AN: 1111964

Other (OTH) AF: 0.000861 AC: 52 AN: 60394

GnomAD4 genome AF: 0.00136 AC: 207 AN: 152290 Hom.: 1 Cov.: 32 AF XY: 0.00163 AC XY: 121 AN XY: 74460

African (AFR) AF: 0.00 AC: 0 AN: 41572

American (AMR) AF: 0.000196 AC: 3 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.0231 AC: 120 AN: 5186

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4826

European-Finnish (FIN) AF: 0.00623 AC: 66 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68022

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.000138 Hom.: 0

Bravo AF: 0.000718

Asia WGS AF: 0.00520 AC: 18 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	13
DANN	Benign	0.74
PhyloP100		4.9
Mutation Taster		=78/22	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs59633770; hg19: chr4-169846127;