19-14054072-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001145028.2(PALM3):c.1600A>G(p.Lys534Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000214 in 1,399,580 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PALM3 NM_001145028.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.66

Genes affected

PALM3 (HGNC:33274): (paralemmin 3) Predicted to enable ATP binding activity. Involved in Toll signaling pathway; negative regulation of cytokine-mediated signaling pathway; and response to lipopolysaccharide. Predicted to be located in cytoplasm and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0345864).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PALM3	NM_001145028.2	c.1600A>G	p.Lys534Glu	missense_variant	7/7	ENST00000669674.2
PALM3	NM_001367327.1	c.1402A>G	p.Lys468Glu	missense_variant	5/5
PALM3	XM_047438763.1	c.1519A>G	p.Lys507Glu	missense_variant	6/6
PALM3	XM_047438764.1	c.1402A>G	p.Lys468Glu	missense_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PALM3	ENST00000669674.2	c.1600A>G	p.Lys534Glu	missense_variant	7/7		NM_001145028.2	A2
PALM3	ENST00000340790.9	c.1555A>G	p.Lys519Glu	missense_variant	6/6	5		P4
PALM3	ENST00000661591.1	c.1480A>G	p.Lys494Glu	missense_variant	4/4			A2
PALM3	ENST00000589048.2	c.1402A>G	p.Lys468Glu	missense_variant	5/5	3		A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000643 AC: 1 AN: 155556 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 82204

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000646

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000214 AC: 3 AN: 1399580 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 690300

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000202

Gnomad4 NFE exome AF: 0.00000185

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 03, 2021

The c.1555A>G (p.K519E) alteration is located in exon 6 (coding exon 6) of the PALM3 gene. This alteration results from a A to G substitution at nucleotide position 1555, causing the lysine (K) at amino acid position 519 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.72
Cadd	Benign	0.13
Dann	Benign	0.60
DEOGEN2	Benign	0.0022	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.052	N
LIST_S2	Benign	0.21	T
M_CAP	Benign	0.0089	T
MetaRNN	Benign	0.035	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.21	N
REVEL	Benign	0.0010
Sift	Benign	0.29	T
Sift4G	Benign	1.0	T
Polyphen		0.0020	B
Vest4		0.059
MutPred		0.25		Loss of ubiquitination at K519 (P = 0.0041);
MVP		0.014
ClinPred		0.053	T
GERP RS		-4.4
Varity_R		0.059
gMVP		0.020

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

Publications

LitVar

Other links and lift over

dbSNP: rs1425490699; hg19: chr19-14164884;