4-168878230-A-G

Variant names:

• chr4-168878230-A-G
• rs864622591
• ENST00000507735.6:c.339A>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_001166110.2(PALLD):​c.339A>G​(p.Pro113Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000145 in 1,382,768 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. P113P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000075 (0 hom., cov: 32)
  • Exomes 𝑓: 8.0e-7 (0 hom.)
• Consequence: PALLD NM_001166110.2 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.33
• 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 -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 4-168878230-A-G is Benign according to our data. Variant chr4-168878230-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 3885290.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-2.33 with no splicing effect.

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.1965-12692A>G		intron	N/A	NP_001159580.1	Q8WX93-9
	PALLD	NM_001166110.2		c.339A>G	p.Pro113Pro	synonymous	Exon 2 of 12	NP_001159582.1	Q8WX93-4
	PALLD	NM_016081.4		c.1965-12692A>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.339A>G	p.Pro113Pro	synonymous	Exon 2 of 12	ENSP00000424016.1	Q8WX93-4
	PALLD	ENST00000505667.6	TSL:1 MANE Select	c.1965-12692A>G		intron	N/A	ENSP00000425556.1	Q8WX93-9
	PALLD	ENST00000261509.10	TSL:1	c.1965-12692A>G		intron	N/A	ENSP00000261509.6	Q8WX93-2

Frequencies

GnomAD3 genomes AF: 0.00000748 AC: 1 AN: 133762 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: 0.0000158

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 8.01e-7 AC: 1 AN: 1249006 Hom.: 0 Cov.: 47 AF XY: 0.00000162 AC XY: 1 AN XY: 616226

African (AFR) AF: 0.00 AC: 0 AN: 25318

American (AMR) AF: 0.00 AC: 0 AN: 30434

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19600

East Asian (EAS) AF: 0.00 AC: 0 AN: 22922

South Asian (SAS) AF: 0.00 AC: 0 AN: 75532

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 23160

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3520

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 999988

Other (OTH) AF: 0.0000206 AC: 1 AN: 48532

GnomAD4 genome AF: 0.00000748 AC: 1 AN: 133762 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 64656

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 34878

American (AMR) AF: 0.00 AC: 0 AN: 13260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3332

East Asian (EAS) AF: 0.00 AC: 0 AN: 4072

South Asian (SAS) AF: 0.00 AC: 0 AN: 3696

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8192

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 282

European-Non Finnish (NFE) AF: 0.0000158 AC: 1 AN: 63388

Other (OTH) AF: 0.00 AC: 0 AN: 1856

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

Asia WGS AF: 0.000290 AC: 1 AN: 3466

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	4.5
DANN	Benign	0.42
PhyloP100		-2.3

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: rs864622591; hg19: chr4-169799381;