Genetic Variant PNMA8B:p.Arg569Leu (chr19-46493760-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_020709.3(PNMA8B):c.1706G>T(p.Arg569Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000429 in 1,352,232 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/16 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. R569W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000086 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000046 ( 0 hom. )

Consequence

PNMA8B
NM_020709.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.179

Variant links:

Genes affected

PNMA8B (HGNC:29206): (PNMA family member 8B)

PNMA8B links:

PPP5D1P (HGNC:):

PPP5D1P links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.11591199).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PNMA8B	NM_020709.3 link	c.1706G>T	p.Arg569Leu	missense_variant	Exon 1 of 1	ENST00000599531.2	NP_065760.1	Q9ULN7-5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PNMA8B	ENST00000599531.2 link	c.1706G>T	p.Arg569Leu	missense_variant	Exon 1 of 1	6	NM_020709.3	ENSP00000473036.1	Q9ULN7-5
PNMA8B	ENST00000594749.1 link	n.165+1955G>T		intron_variant	Intron 1 of 1	5
PPP5D1P	ENST00000602017.7 link	n.378-12320G>T		intron_variant	Intron 3 of 3	3
PPP5D1P	ENST00000702671.1 link	n.394-12320G>T		intron_variant	Intron 4 of 4

Frequencies

GnomAD3 genomes

AF:

0.00000864

AC:

AN:

115784

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000208

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000461

AC:

AN:

1236448

Hom.:

Cov.:

AF XY:

0.0000415

AC XY:

AN XY:

602562

show subpopulations

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:

0.0000554

Gnomad4 OTH exome

AF:

0.0000196

GnomAD4 genome

AF:

0.00000864

AC:

AN:

115784

Hom.:

Cov.:

AF XY:

0.0000175

AC XY:

AN XY:

57106

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000208

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ExAC

AF:

0.0000116

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 07, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1706G>T (p.R569L) alteration is located in exon 1 (coding exon 1) of the PNMAL2 gene. This alteration results from a G to T substitution at nucleotide position 1706, causing the arginine (R) at amino acid position 569 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

0.34

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.68

CADD

Benign

DANN

Benign

0.95

FATHMM_MKL

Benign

0.037

LIST_S2

Benign

0.41

M_CAP

Benign

0.022

MetaRNN

Benign

0.12

PrimateAI

Uncertain

0.76

Sift4G

Pathogenic

0.0

Vest4

0.15

MVP

0.45

GERP RS

-1.2

Varity_R

0.068

gMVP

0.11

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.

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