rs201995410

Positions:

chr19-727021-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_002579.3(PALM):c.71G>A(p.Arg24Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00111 in 1,194,832 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R24W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00053 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0012 ( 0 hom. )

Consequence

PALM
NM_002579.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 2.63

Variant links:

Genes affected

PALM (HGNC:8594): (paralemmin) This gene encodes a member of the paralemmin protein family. The product of this gene is a prenylated and palmitoylated phosphoprotein that associates with the cytoplasmic face of plasma membranes and is implicated in plasma membrane dynamics in neurons and other cell types. Several alternatively spliced transcript variants have been identified, but the full-length nature of only two transcript variants has been determined. [provided by RefSeq, Jul 2008]

PALM links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.045523226).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PALM	NM_002579.3 linkuse as main transcript	c.71G>A	p.Arg24Gln	missense_variant	3/9	ENST00000338448.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PALM	ENST00000338448.10 linkuse as main transcript	c.71G>A	p.Arg24Gln	missense_variant	3/9	1	NM_002579.3	P1	O75781-1

Frequencies

GnomAD3 genomes

AF:

0.000529

AC:

AN:

143584

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000101

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000690

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000248

Gnomad FIN

AF:

0.000326

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000977

Gnomad OTH

AF:

0.00149

GnomAD3 exomes

AF:

0.000416

AC:

AN:

146634

Hom.:

AF XY:

0.000484

AC XY:

AN XY:

78552

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000204

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000132

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000963

Gnomad OTH exome

AF:

0.000238

GnomAD4 exome

AF:

0.00119

AC:

1249

AN:

1051104

Hom.:

Cov.:

AF XY:

0.00114

AC XY:

592

AN XY:

520318

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000174

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000134

Gnomad4 FIN exome

AF:

0.000529

Gnomad4 NFE exome

AF:

0.00144

Gnomad4 OTH exome

AF:

0.000849

GnomAD4 genome

AF:

0.000529

AC:

AN:

143728

Hom.:

Cov.:

AF XY:

0.000629

AC XY:

AN XY:

69956

show subpopulations

Gnomad4 AFR

AF:

0.000101

Gnomad4 AMR

AF:

0.0000689

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000247

Gnomad4 FIN

AF:

0.000326

Gnomad4 NFE

AF:

0.000977

Gnomad4 OTH

AF:

0.00147

Alfa

AF:

0.000830

Hom.:

Bravo

AF:

0.000461

ESP6500AA

AF:

0.000267

AC:

ESP6500EA

AF:

0.00108

AC:

ExAC

AF:

0.000202

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 09, 2021

The c.71G>A (p.R24Q) alteration is located in exon 3 (coding exon 3) of the PALM gene. This alteration results from a G to A substitution at nucleotide position 71, causing the arginine (R) at amino acid position 24 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

atypical cerebral palsy

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

TIDEX, University of British Columbia

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 03, 2023

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 24 of the PALM protein (p.Arg24Gln). This variant is present in population databases (rs201995410, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 431724). This missense change has been observed in individual(s) with loss or impairment of motor function (PMID: 30542205). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.52

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.30

.;T

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.29

FATHMM_MKL

Uncertain

0.77

LIST_S2

Uncertain

0.91

D;D

M_CAP

Benign

0.060

MetaRNN

Benign

0.046

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.3

M;M

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.37

PROVEAN

Uncertain

-2.6

D;D

REVEL

Benign

0.058

Sift

Benign

0.073

T;T

Sift4G

Benign

0.14

T;T

Polyphen

0.88

P;P

Vest4

0.32

MVP

0.37

MPC

0.34

ClinPred

0.096

GERP RS

1.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.10

gMVP

0.13

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over