ENST00000507735.6:c.254C>T

Variant names:

• chr4-168878145-C-T
• rs864622140
• ENST00000507735.6:c.254C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The ENST00000507735.6(PALLD):​c.254C>T​(p.Ser85Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000517 in 1,488,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/18 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. S85S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000054 (0 hom.)
• Consequence: PALLD ENST00000507735.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 6.77
• 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=0.24887836).
• BS2: High AC in GnomAd4 at 5 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PALLD	NM_001166108.2	MANE Select	c.1965-12777C>T		intron	N/A	NP_001159580.1	Q8WX93-9
	PALLD	NM_001166110.2		c.254C>T	p.Ser85Leu	missense	Exon 2 of 12	NP_001159582.1	Q8WX93-4
	PALLD	NM_016081.4		c.1965-12777C>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.254C>T	p.Ser85Leu	missense	Exon 2 of 12	ENSP00000424016.1	Q8WX93-4
	PALLD	ENST00000505667.6	TSL:1 MANE Select	c.1965-12777C>T		intron	N/A	ENSP00000425556.1	Q8WX93-9
	PALLD	ENST00000261509.10	TSL:1	c.1965-12777C>T		intron	N/A	ENSP00000261509.6	Q8WX93-2

Frequencies

GnomAD3 genomes AF: 0.0000330 AC: 5 AN: 151742 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000737

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000446 AC: 4 AN: 89598 AF XY: 0.0000198

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: 0.000121

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000538 AC: 72 AN: 1337082 Hom.: 0 Cov.: 31 AF XY: 0.0000486 AC XY: 32 AN XY: 658996

African (AFR) AF: 0.00 AC: 0 AN: 27084

American (AMR) AF: 0.00 AC: 0 AN: 30028

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23572

East Asian (EAS) AF: 0.0000654 AC: 2 AN: 30566

South Asian (SAS) AF: 0.00 AC: 0 AN: 74426

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33140

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4040

European-Non Finnish (NFE) AF: 0.0000661 AC: 70 AN: 1058636

Other (OTH) AF: 0.00 AC: 0 AN: 55590

GnomAD4 genome AF: 0.0000330 AC: 5 AN: 151742 Hom.: 0 Cov.: 32 AF XY: 0.0000405 AC XY: 3 AN XY: 74102

African (AFR) AF: 0.00 AC: 0 AN: 41298

American (AMR) AF: 0.00 AC: 0 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5146

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10544

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

European-Non Finnish (NFE) AF: 0.0000737 AC: 5 AN: 67886

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

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	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	0.17
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	19
DANN	Benign	0.90
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.28
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.76	T
M_CAP	Pathogenic	0.30	D
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.92	T
PhyloP100		6.8
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.16
Sift	Benign	0.48	T
Sift4G	Benign	0.25	T
Vest4		0.26
MVP		0.55
ClinPred		0.13	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Mutation Taster		=65/35	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: rs864622140; hg19: chr4-169799296;