19-726146-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_002579.3(PALM):​c.14C>T​(p.Ala5Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000843 in 1,612,734 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000085 ( 0 hom. )

Consequence

PALM
NM_002579.3 missense

Scores

19

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: -1.89
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.011496931).
BP6
Variant 19-726146-C-T is Benign according to our data. Variant chr19-726146-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1981142.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PALMNM_002579.3 linkc.14C>T p.Ala5Val missense_variant 2/9 ENST00000338448.10 NP_002570.2 O75781-1A0A024R1Y6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PALMENST00000338448.10 linkc.14C>T p.Ala5Val missense_variant 2/91 NM_002579.3 ENSP00000341911.4 O75781-1

Frequencies

GnomAD3 genomes
AF:
0.0000788
AC:
12
AN:
152228
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000386
Gnomad SAS
AF:
0.000414
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000103
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000112
AC:
28
AN:
250624
Hom.:
0
AF XY:
0.000140
AC XY:
19
AN XY:
135694
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000868
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.000457
Gnomad FIN exome
AF:
0.0000462
Gnomad NFE exome
AF:
0.0000707
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000849
AC:
124
AN:
1460388
Hom.:
0
Cov.:
30
AF XY:
0.0000908
AC XY:
66
AN XY:
726600
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000895
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.000499
Gnomad4 FIN exome
AF:
0.0000378
Gnomad4 NFE exome
AF:
0.0000585
Gnomad4 OTH exome
AF:
0.000133
GnomAD4 genome
AF:
0.0000788
AC:
12
AN:
152346
Hom.:
0
Cov.:
32
AF XY:
0.0000805
AC XY:
6
AN XY:
74502
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000386
Gnomad4 SAS
AF:
0.000414
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000103
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000444
Hom.:
0
Bravo
AF:
0.0000831
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.000157
AC:
19
EpiCase
AF:
0.000327
EpiControl
AF:
0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 04, 2024This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 5 of the PALM protein (p.Ala5Val). This variant is present in population databases (rs372771354, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with PALM-related conditions. ClinVar contains an entry for this variant (Variation ID: 1981142). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -
not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsNov 22, 2021This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.093
BayesDel_addAF
Benign
-0.59
T
BayesDel_noAF
Benign
-0.75
CADD
Benign
4.9
DANN
Benign
0.86
DEOGEN2
Benign
0.043
.;T;.
Eigen
Benign
-1.7
Eigen_PC
Benign
-1.7
FATHMM_MKL
Benign
0.010
N
LIST_S2
Benign
0.51
T;T;.
M_CAP
Benign
0.0092
T
MetaRNN
Benign
0.011
T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
-0.11
N;N;.
PrimateAI
Benign
0.47
T
PROVEAN
Benign
-0.70
N;N;.
REVEL
Benign
0.019
Sift
Benign
0.60
T;T;.
Sift4G
Benign
0.85
T;T;.
Polyphen
0.0010
B;B;.
Vest4
0.14
MVP
0.19
MPC
0.14
ClinPred
0.0053
T
GERP RS
-4.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.038
gMVP
0.17

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

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

Other links and lift over

dbSNP: rs372771354; hg19: chr19-726146; COSMIC: COSV52770735; COSMIC: COSV52770735; API