X-153058067-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_013364.6(PNMA3):c.1012G>A(p.Ala338Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,097,998 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples 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: 25)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: PNMA3 NM_013364.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0820

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0664832).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PNMA3	NM_013364.6	c.1012G>A	p.Ala338Thr	missense_variant	2/2	ENST00000593810.3
PNMA3	NM_001282535.2	c.1012G>A	p.Ala338Thr	missense_variant	2/3
PNMA3	XR_938508.4	n.1287G>A		non_coding_transcript_exon_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PNMA3	ENST00000593810.3	c.1012G>A	p.Ala338Thr	missense_variant	2/2		NM_013364.6	P1
PNMA3	ENST00000619635.1	c.1012G>A	p.Ala338Thr	missense_variant	2/3	1
PNMA3	ENST00000424805.1	c.1012G>A	p.Ala338Thr	missense_variant, NMD_transcript_variant	2/3	5

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD3 exomes AF: 0.00000549 AC: 1 AN: 182298 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 67282

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: 0.0000526

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097998 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 363392

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: 0.0000185

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 25

ExAC AF: 0.00000824 AC: 1

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

Apr 06, 2023

The c.1012G>A (p.A338T) 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 1012, causing the alanine (A) at amino acid position 338 to be replaced by a threonine (T). 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	0.11
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.95
Cadd	Benign	8.7
Dann	Benign	0.19
FATHMM_MKL	Benign	0.0092	N
LIST_S2	Benign	0.45	T;T
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.066	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.81	L;L
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.43	T
Sift4G	Benign	0.26	T;T
Polyphen		0.050	.;B
Vest4		0.047
MutPred		0.14		Gain of glycosylation at A338 (P = 0.1227);Gain of glycosylation at A338 (P = 0.1227);
MVP		0.77
ClinPred		0.063	T
GERP RS		-0.27
Varity_R		0.073
gMVP		0.21

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs782395896; hg19: chrX-152226424;