19-14054081-C-T

Variant names:

• chr19-14054081-C-T
• rs1327166701
• NM_001145028.2:c.1591G>A

Variant summary

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

The NM_001145028.2(PALM3):​c.1591G>A​(p.Glu531Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,399,606 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PALM3 NM_001145028.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.00200

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=0.0518333).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PALM3	NM_001145028.2	c.1591G>A	p.Glu531Lys	missense_variant	Exon 7 of 7	ENST00000669674.2	NP_001138500.2
PALM3	NM_001367327.1	c.1393G>A	p.Glu465Lys	missense_variant	Exon 5 of 5		NP_001354256.1
PALM3	XM_047438763.1	c.1510G>A	p.Glu504Lys	missense_variant	Exon 6 of 6		XP_047294719.1
PALM3	XM_047438764.1	c.1393G>A	p.Glu465Lys	missense_variant	Exon 5 of 5		XP_047294720.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PALM3	ENST00000669674.2	c.1591G>A	p.Glu531Lys	missense_variant	Exon 7 of 7		NM_001145028.2	ENSP00000499271.1
PALM3	ENST00000340790.9	c.1546G>A	p.Glu516Lys	missense_variant	Exon 6 of 6	5		ENSP00000344996.3
PALM3	ENST00000661591.1	c.1471G>A	p.Glu491Lys	missense_variant	Exon 4 of 4			ENSP00000499248.1
PALM3	ENST00000589048.2	c.1393G>A	p.Glu465Lys	missense_variant	Exon 5 of 5	3		ENSP00000465701.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1399606 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 690304

Gnomad4 AFR exome AF: 0.0000317

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: 0.00

Gnomad4 NFE exome AF: 9.27e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 07, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1546G>A (p.E516K) alteration is located in exon 6 (coding exon 6) of the PALM3 gene. This alteration results from a G to A substitution at nucleotide position 1546, causing the glutamic acid (E) at amino acid position 516 to be replaced by a lysine (K). 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	0.084
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.88
DANN	Benign	0.74
DEOGEN2	Benign	0.00071	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.074	N
LIST_S2	Benign	0.49	T
M_CAP	Benign	0.0099	T
MetaRNN	Benign	0.052	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.71	N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.57	N
REVEL	Benign	0.0080
Sift	Benign	0.38	T
Sift4G	Benign	0.20	T
Polyphen		0.0010	B
Vest4		0.049
MutPred		0.31		Gain of ubiquitination at E516 (P = 0.0114);
MVP		0.014
ClinPred		0.023	T
GERP RS		-0.086
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.034
gMVP		0.029

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: rs1327166701; hg19: chr19-14164893;