chr19-14054056-T-A

Position:

• chr19-14054056-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001145028.2(PALM3):​c.1616A>T​(p.Glu539Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000786 in 1,399,570 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 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: 0.0000079 (0 hom.)
• Consequence: PALM3 NM_001145028.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.32

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12370175).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PALM3	NM_001145028.2	c.1616A>T	p.Glu539Val	missense_variant	7/7	ENST00000669674.2	NP_001138500.2
PALM3	NM_001367327.1	c.1418A>T	p.Glu473Val	missense_variant	5/5		NP_001354256.1
PALM3	XM_047438763.1	c.1535A>T	p.Glu512Val	missense_variant	6/6		XP_047294719.1
PALM3	XM_047438764.1	c.1418A>T	p.Glu473Val	missense_variant	5/5		XP_047294720.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PALM3	ENST00000669674.2	c.1616A>T	p.Glu539Val	missense_variant	7/7		NM_001145028.2	ENSP00000499271.1
PALM3	ENST00000340790.9	c.1571A>T	p.Glu524Val	missense_variant	6/6	5		ENSP00000344996.3
PALM3	ENST00000661591.1	c.1496A>T	p.Glu499Val	missense_variant	4/4			ENSP00000499248.1
PALM3	ENST00000589048.2	c.1418A>T	p.Glu473Val	missense_variant	5/5	3		ENSP00000465701.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000786 AC: 11 AN: 1399570 Hom.: 0 Cov.: 31 AF XY: 0.00000869 AC XY: 6 AN XY: 690298

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: 0.00

Gnomad4 NFE exome AF: 0.00000927

Gnomad4 OTH exome AF: 0.0000172

GnomAD4 genome Cov.: 32

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

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

Sep 08, 2024

The c.1571A>T (p.E524V) alteration is located in exon 6 (coding exon 6) of the PALM3 gene. This alteration results from a A to T substitution at nucleotide position 1571, causing the glutamic acid (E) at amino acid position 524 to be replaced by a valine (V). 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	0.10
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	4.2
DANN	Benign	0.96
DEOGEN2	Benign	0.010	T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.41	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.065
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.038	D
Polyphen		0.98	D
Vest4		0.12
MutPred		0.31		Gain of sheet (P = 0.0043);
MVP		0.14
ClinPred		0.35	T
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.11
gMVP		0.050

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: rs770902168; hg19: chr19-14164868;