4-168877969-C-T

Variant names:

• chr4-168877969-C-T
• rs528879194
• ENST00000507735.6:c.78C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The ENST00000507735.6(PALLD):​c.78C>T​(p.Phe26Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00085 in 1,502,058 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0045 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00044 (5 hom.)
• Consequence: PALLD ENST00000507735.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.53
• 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant 4-168877969-C-T is Benign according to our data. Variant chr4-168877969-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 215491.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=3.53 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.000439 (593/1350122) while in subpopulation AFR AF = 0.0179 (494/27594). AF 95% confidence interval is 0.0166. There are 5 homozygotes in GnomAdExome4. There are 251 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 684 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PALLD	NM_001166108.2	MANE Select	c.1965-12953C>T		intron	N/A	NP_001159580.1
	PALLD	NM_001166110.2		c.78C>T	p.Phe26Phe	synonymous	Exon 2 of 12	NP_001159582.1
	PALLD	NM_016081.4		c.1965-12953C>T		intron	N/A	NP_057165.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PALLD	ENST00000507735.6	TSL:1	c.78C>T	p.Phe26Phe	synonymous	Exon 2 of 12	ENSP00000424016.1
	PALLD	ENST00000505667.6	TSL:1 MANE Select	c.1965-12953C>T		intron	N/A	ENSP00000425556.1
	PALLD	ENST00000261509.10	TSL:1	c.1965-12953C>T		intron	N/A	ENSP00000261509.6

Frequencies

GnomAD3 genomes AF: 0.00450 AC: 683 AN: 151826 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0157

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00528

GnomAD2 exomes AF: 0.000320 AC: 32 AN: 99968 AF XY: 0.000321

Gnomad AFR exome AF: 0.0135

Gnomad AMR exome AF: 0.000387

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000439 AC: 593 AN: 1350122 Hom.: 5 Cov.: 31 AF XY: 0.000377 AC XY: 251 AN XY: 666052

African (AFR) AF: 0.0179 AC: 494 AN: 27594

American (AMR) AF: 0.000649 AC: 21 AN: 32376

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24026

East Asian (EAS) AF: 0.00 AC: 0 AN: 31458

South Asian (SAS) AF: 0.0000131 AC: 1 AN: 76476

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33274

Middle Eastern (MID) AF: 0.00147 AC: 8 AN: 5448

European-Non Finnish (NFE) AF: 0.00000564 AC: 6 AN: 1063156

Other (OTH) AF: 0.00112 AC: 63 AN: 56314

GnomAD4 genome AF: 0.00450 AC: 684 AN: 151936 Hom.: 1 Cov.: 32 AF XY: 0.00452 AC XY: 336 AN XY: 74284

African (AFR) AF: 0.0157 AC: 651 AN: 41508

American (AMR) AF: 0.00124 AC: 19 AN: 15274

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5150

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10470

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67926

Other (OTH) AF: 0.00522 AC: 11 AN: 2108

Alfa AF: 0.00204 Hom.: 0

Bravo AF: 0.00490

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	1	Pancreatic adenocarcinoma (1)
-	-	1	Pancreatic cancer, susceptibility to, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	22
DANN	Benign	0.95
PhyloP100		3.5
Mutation Taster		=96/4	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: rs528879194; hg19: chr4-169799120;