chr4-168878249-C-T

Variant names:

• chr4-168878249-C-T
• rs925242863
• ENST00000507735.6:c.358C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001166110.2(PALLD):​c.358C>T​(p.Pro120Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000204 in 1,522,990 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 Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P120P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: PALLD NM_001166110.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.386
• 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.04674223).
• BS2: High AC in GnomAd4 at 6 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.1965-12673C>T		intron	N/A	NP_001159580.1
	PALLD	NM_001166110.2		c.358C>T	p.Pro120Ser	missense	Exon 2 of 12	NP_001159582.1
	PALLD	NM_016081.4		c.1965-12673C>T		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.358C>T	p.Pro120Ser	missense	Exon 2 of 12	ENSP00000424016.1
	PALLD	ENST00000505667.6	TSL:1 MANE Select	c.1965-12673C>T		intron	N/A	ENSP00000425556.1
	PALLD	ENST00000261509.10	TSL:1	c.1965-12673C>T		intron	N/A	ENSP00000261509.6

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152114 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000255 AC: 3 AN: 117616 AF XY: 0.0000154

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000433

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000455

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000182 AC: 25 AN: 1370876 Hom.: 0 Cov.: 46 AF XY: 0.0000177 AC XY: 12 AN XY: 676266

African (AFR) AF: 0.0000335 AC: 1 AN: 29840

American (AMR) AF: 0.0000288 AC: 1 AN: 34778

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24754

East Asian (EAS) AF: 0.00 AC: 0 AN: 34280

South Asian (SAS) AF: 0.00 AC: 0 AN: 77604

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33434

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4330

European-Non Finnish (NFE) AF: 0.0000205 AC: 22 AN: 1074546

Other (OTH) AF: 0.0000174 AC: 1 AN: 57310

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152114 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74322

African (AFR) AF: 0.0000241 AC: 1 AN: 41420

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000340

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

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	0.095
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	1.7
DANN	Benign	0.83
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.47	T
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.047	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.39
PROVEAN	Benign	-0.55	N
REVEL	Benign	0.058
Sift	Benign	0.85	T
Sift4G	Benign	0.25	T
Vest4		0.060
MVP		0.13
ClinPred		0.014	T
GERP RS		-3.0
Mutation Taster		=95/5	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: rs925242863; hg19: chr4-169799400;