19-14055064-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001145028.2(PALM3):c.608C>T(p.Pro203Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00187 in 1,551,592 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0019 ( 4 hom. )

Consequence

PALM3
NM_001145028.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.269

Publications

4 publications found

Variant links:

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]

PALM3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004764825).

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PALM3	NM_001145028.2 link	c.608C>T	p.Pro203Leu	missense_variant	Exon 7 of 7	ENST00000669674.2	NP_001138500.2	A6NDB9
PALM3	NM_001367327.1 link	c.410C>T	p.Pro137Leu	missense_variant	Exon 5 of 5		NP_001354256.1
PALM3	XM_047438763.1 link	c.527C>T	p.Pro176Leu	missense_variant	Exon 6 of 6		XP_047294719.1
PALM3	XM_047438764.1 link	c.410C>T	p.Pro137Leu	missense_variant	Exon 5 of 5		XP_047294720.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PALM3	ENST00000669674.2 link	c.608C>T	p.Pro203Leu	missense_variant	Exon 7 of 7		NM_001145028.2	ENSP00000499271.1	A0A590UJ36
PALM3	ENST00000340790.9 link	c.563C>T	p.Pro188Leu	missense_variant	Exon 6 of 6	5		ENSP00000344996.3	A6NDB9
PALM3	ENST00000661591.1 link	c.488C>T	p.Pro163Leu	missense_variant	Exon 4 of 4			ENSP00000499248.1	A0A590UJ23
PALM3	ENST00000589048.2 link	c.410C>T	p.Pro137Leu	missense_variant	Exon 5 of 5	3		ENSP00000465701.2	K7EKN5

Frequencies

GnomAD3 genomes

AF:

0.00138

AC:

210

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000410

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00301

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00235

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00129

AC:

200

AN:

154738

AF XY:

0.00138

show subpopulations

Gnomad AFR exome

AF:

0.000256

Gnomad AMR exome

AF:

0.000243

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00413

Gnomad NFE exome

AF:

0.00207

Gnomad OTH exome

AF:

0.000459

GnomAD4 exome

AF:

0.00193

AC:

2699

AN:

1399266

Hom.:

Cov.:

AF XY:

0.00188

AC XY:

1299

AN XY:

690150

show subpopulations

African (AFR)

AF:

0.000190

AC:

AN:

31598

American (AMR)

AF:

0.000224

AC:

AN:

35702

Ashkenazi Jewish (ASJ)

AF:

0.0000794

AC:

AN:

25176

East Asian (EAS)

AF:

0.00

AC:

AN:

35738

South Asian (SAS)

AF:

0.00

AC:

AN:

79226

European-Finnish (FIN)

AF:

0.00433

AC:

213

AN:

49188

Middle Eastern (MID)

AF:

0.000176

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

0.00222

AC:

2399

AN:

1078932

Other (OTH)

AF:

0.00121

AC:

AN:

58008

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

179

358

537

716

895

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

184

276

368

460

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00138

AC:

210

AN:

152326

Hom.:

Cov.:

AF XY:

0.00125

AC XY:

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.000409

AC:

AN:

41574

American (AMR)

AF:

0.00

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00301

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00235

AC:

160

AN:

68034

Other (OTH)

AF:

0.000473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00124

Hom.:

Bravo

AF:

0.00106

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00130

AC:

ExAC

AF:

0.000500

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 23, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.563C>T (p.P188L) alteration is located in exon 6 (coding exon 6) of the PALM3 gene. This alteration results from a C to T substitution at nucleotide position 563, causing the proline (P) at amino acid position 188 to be replaced by a leucine (L). 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

0.088

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Benign

0.81

DEOGEN2

Benign

0.0025

T;T

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.82

FATHMM_MKL

Benign

0.27

LIST_S2

Benign

0.77

T;.

M_CAP

Benign

0.014

MetaRNN

Benign

0.0048

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.6

L;.

PhyloP100

0.27

PrimateAI

Benign

0.37

PROVEAN

Benign

-2.2

N;.

REVEL

Benign

0.049

Sift

Uncertain

0.0010

D;.

Sift4G

Benign

0.13

T;T

Polyphen

0.36

B;.

Vest4

0.087

MVP

0.23

ClinPred

0.019

GERP RS

-2.1

Varity_R

0.12

gMVP

0.083

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over