Genetic Variant PNMA3:p.Arg410His (chrX-153058284-G-A) – 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.1229G>A(p.Arg410His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000546 in 1,098,037 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 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: not found (cov: 24)

Exomes 𝑓: 0.0000055 ( 0 hom. 2 hem. )

Consequence

PNMA3
NM_013364.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0780

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=0.047080845).

BS2

High Hemizygotes in GnomAdExome4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PNMA3	NM_013364.6 link	c.1229G>A	p.Arg410His	missense_variant	Exon 2 of 2	ENST00000593810.3	NP_037496.4	Q9UL41-1
PNMA3	NM_001282535.2 link	c.1229G>A	p.Arg410His	missense_variant	Exon 2 of 3		NP_001269464.1	Q9UL41-2
PNMA3	XR_938508.4 link	n.1504G>A		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.1229G>A	p.Arg410His	missense_variant	Exon 2 of 2	6	NM_013364.6	ENSP00000469445.1	Q9UL41-1
PNMA3	ENST00000619635.1 link	c.1229G>A	p.Arg410His	missense_variant	Exon 2 of 3	1		ENSP00000480719.1	Q9UL41-2
PNMA3	ENST00000424805.1 link	n.1229G>A		non_coding_transcript_exon_variant	Exon 2 of 3	5		ENSP00000390576.1	Q9UL41-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000164

AC:

AN:

183155

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

67771

show subpopulations

Gnomad AFR exome

AF:

0.0000765

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000722

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000122

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000546

AC:

AN:

1098037

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

363397

show subpopulations

Gnomad4 AFR exome

AF:

0.0000379

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000185

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000475

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 22, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1229G>A (p.R410H) alteration is located in exon 2 (coding exon 1) of the PNMA3 gene. This alteration results from a G to A substitution at nucleotide position 1229, causing the arginine (R) at amino acid position 410 to be replaced by a histidine (H). 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

0.066

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-1.1

CADD

Benign

9.6

DANN

Benign

0.96

DEOGEN2

Benign

0.0060

.;T

FATHMM_MKL

Benign

0.0014

LIST_S2

Benign

0.53

T;T

M_CAP

Benign

0.0027

MetaRNN

Benign

0.047

T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-0.20

N;N

PrimateAI

Benign

0.33

Sift4G

Benign

0.58

T;T

Polyphen

0.0

.;B

Vest4

0.067

MutPred

0.34

Loss of solvent accessibility (P = 0.0128);Loss of solvent accessibility (P = 0.0128);

MVP

0.11

ClinPred

0.010

GERP RS

-0.99

Varity_R

0.038

gMVP

0.31

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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