Genetic Variant PNMA3:p.Ala338Thr (chrX-153058067-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_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

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0820

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 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 rank	MANE	Protein	UniProt
PNMA3	NM_013364.6 link	c.1012G>A	p.Ala338Thr	missense_variant	Exon 2 of 2	ENST00000593810.3	NP_037496.4	Q9UL41-1
PNMA3	NM_001282535.2 link	c.1012G>A	p.Ala338Thr	missense_variant	Exon 2 of 3		NP_001269464.1	Q9UL41-2
PNMA3	XR_938508.4 link	n.1287G>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.1012G>A	p.Ala338Thr	missense_variant	Exon 2 of 2	6	NM_013364.6	ENSP00000469445.1	Q9UL41-1
PNMA3	ENST00000619635.1 link	c.1012G>A	p.Ala338Thr	missense_variant	Exon 2 of 3	1		ENSP00000480719.1	Q9UL41-2
PNMA3	ENST00000424805.1 link	n.1012G>A		non_coding_transcript_exon_variant	Exon 2 of 3	5		ENSP00000390576.1	Q9UL41-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000549

AC:

AN:

182298

Hom.:

AF XY:

0.00

AC XY:

AN XY:

67282

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:

0.0000526

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:

AN:

1097998

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

363392

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:

0.0000185

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 06, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

BayesDel_noAF

Benign

-0.95

CADD

Benign

8.7

DANN

Benign

0.19

DEOGEN2

Benign

0.042

.;T

FATHMM_MKL

Benign

0.0092

LIST_S2

Benign

0.45

T;T

M_CAP

Benign

0.0047

MetaRNN

Benign

0.066

T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.81

L;L

PrimateAI

Benign

0.43

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

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

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