Genetic Variant PNMA3:p.Pro342Ala (chrX-153058079-C-G) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_013364.6(PNMA3):c.1024C>G(p.Pro342Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000014 in 1,210,405 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 0 hem., cov: 24)

Exomes 𝑓: 0.000014 ( 0 hom. 3 hem. )

Consequence

PNMA3
NM_013364.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.558

Variant links:

Genes affected

PNMA3 (HGNC:18742): (PNMA family member 3) The protein encoded by this gene belongs to the paraneoplastic antigen MA (PNMA) family, which shares homology with retroviral Gag proteins. The PNMA antigens are highly expressed in the brain and also in a range of tumors associated with serious neurological phenotypes. PMID:16407312 reports the presence of a functional -1 ribosomal frameshift signal (consisting of a heptanucleotide shift motif followed 3' by a pseudoknot structure) in this gene, however, the frame-shifted product has not been characterized. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2013]

PNMA3 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.051955014).

BS2

High Hemizygotes in GnomAdExome4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PNMA3	NM_013364.6 link	c.1024C>G	p.Pro342Ala	missense_variant	Exon 2 of 2	ENST00000593810.3	NP_037496.4	Q9UL41-1
PNMA3	NM_001282535.2 link	c.1024C>G	p.Pro342Ala	missense_variant	Exon 2 of 3		NP_001269464.1	Q9UL41-2
PNMA3	XR_938508.4 link	n.1299C>G		non_coding_transcript_exon_variant	Exon 2 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PNMA3	ENST00000593810.3 link	c.1024C>G	p.Pro342Ala	missense_variant	Exon 2 of 2	6	NM_013364.6	ENSP00000469445.1	Q9UL41-1
PNMA3	ENST00000619635.1 link	c.1024C>G	p.Pro342Ala	missense_variant	Exon 2 of 3	1		ENSP00000480719.1	Q9UL41-2
PNMA3	ENST00000424805.1 link	n.1024C>G		non_coding_transcript_exon_variant	Exon 2 of 3	5		ENSP00000390576.1	Q9UL41-1

Frequencies

GnomAD3 genomes

AF:

0.0000178

AC:

AN:

112554

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34694

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:

0.0000376

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000550

AC:

AN:

181917

Hom.:

AF XY:

0.00

AC XY:

AN XY:

67121

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000123

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1097851

Hom.:

Cov.:

AF XY:

0.00000826

AC XY:

AN XY:

363265

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:

0.0000178

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000178

AC:

AN:

112554

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34694

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:

0.0000376

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 21, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1024C>G (p.P342A) alteration is located in exon 2 (coding exon 1) of the PNMA3 gene. This alteration results from a C to G substitution at nucleotide position 1024, causing the proline (P) at amino acid position 342 to be replaced by an alanine (A). 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

0.071

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-1.0

CADD

Benign

3.8

DANN

Benign

0.11

DEOGEN2

Benign

0.024

.;T

FATHMM_MKL

Benign

0.0050

LIST_S2

Benign

0.54

T;T

M_CAP

Benign

0.0016

MetaRNN

Benign

0.052

T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.81

L;L

PrimateAI

Benign

0.40

Sift4G

Benign

0.75

T;T

Polyphen

0.0030

.;B

Vest4

0.082

MVP

0.061

ClinPred

0.018

GERP RS

-0.069

Varity_R

0.027

gMVP

0.32

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.18

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