chr4-168903808-A-C

Variant names:

• chr4-168903808-A-C
• rs1553973196
• NM_001166108.2:c.2524A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001166108.2(PALLD):​c.2524A>C​(p.Thr842Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,458 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T842A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PALLD NM_001166108.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.51
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2047028).

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.2524A>C	p.Thr842Pro	missense	Exon 15 of 22	NP_001159580.1
	PALLD	NM_016081.4		c.2473A>C	p.Thr825Pro	missense	Exon 14 of 21	NP_057165.3
	PALLD	NM_001166109.2		c.1327A>C	p.Thr443Pro	missense	Exon 13 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.2524A>C	p.Thr842Pro	missense	Exon 15 of 22	ENSP00000425556.1
	PALLD	ENST00000261509.10	TSL:1	c.2473A>C	p.Thr825Pro	missense	Exon 14 of 21	ENSP00000261509.6
	PALLD	ENST00000507735.6	TSL:1	c.1012A>C	p.Thr338Pro	missense	Exon 6 of 12	ENSP00000424016.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459458 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 726214

African (AFR) AF: 0.00 AC: 0 AN: 33426

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.00 AC: 0 AN: 86228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1109816

Other (OTH) AF: 0.00 AC: 0 AN: 60300

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Benign	0.0078	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	18
DANN	Benign	0.96
DEOGEN2	Benign	0.035	T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.38
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.073	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.85	T
PhyloP100		2.5
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.37
Sift	Benign	0.065	T
Sift4G	Uncertain	0.059	T
Vest4		0.48
MVP		0.43
MPC		0.44
ClinPred		0.34	T
GERP RS		4.2
gMVP		0.69
Mutation Taster		=77/23	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: rs1553973196; hg19: chr4-169824959;