X-153058284-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0780

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.047080845).
• BS2: High Hemizygotes in GnomAdExome at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PNMA3	NM_013364.6	c.1229G>A	p.Arg410His	missense_variant	2/2	ENST00000593810.3
PNMA3	NM_001282535.2	c.1229G>A	p.Arg410His	missense_variant	2/3
PNMA3	XR_938508.4	n.1504G>A		non_coding_transcript_exon_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PNMA3	ENST00000593810.3	c.1229G>A	p.Arg410His	missense_variant	2/2		NM_013364.6	P1
PNMA3	ENST00000619635.1	c.1229G>A	p.Arg410His	missense_variant	2/3	1
PNMA3	ENST00000424805.1	c.1229G>A	p.Arg410His	missense_variant, NMD_transcript_variant	2/3	5

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD3 exomes AF: 0.0000164 AC: 3 AN: 183155 Hom.: 0 AF XY: 0.0000295 AC XY: 2 AN XY: 67771

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: 6 AN: 1098037 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 2 AN XY: 363397

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.: 24

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 22, 2023

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	T
BayesDel_noAF	Benign	-1.1
Cadd	Benign	9.6
Dann	Benign	0.96
FATHMM_MKL	Benign	0.0014	N
LIST_S2	Benign	0.53	T;T
M_CAP	Benign	0.0027	T
MetaRNN	Benign	0.047	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.20	N;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.33	T
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	T
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

Other links and lift over

dbSNP: rs782746085; hg19: chrX-152226641; COSMIC: COSV64721943;