X-153058146-G-A

Variant names:

• chrX-153058146-G-A
• NM_013364.6:c.1091G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_013364.6(PNMA3):​c.1091G>A​(p.Gly364Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000182 in 1,097,852 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: 24)
  • Exomes 𝑓: 0.0000018 (0 hom. 0 hem.)
• Consequence: PNMA3 NM_013364.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.409

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11210662).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PNMA3	NM_013364.6	c.1091G>A	p.Gly364Glu	missense_variant	Exon 2 of 2	ENST00000593810.3	NP_037496.4
PNMA3	NM_001282535.2	c.1091G>A	p.Gly364Glu	missense_variant	Exon 2 of 3		NP_001269464.1
PNMA3	XR_938508.4	n.1366G>A		non_coding_transcript_exon_variant	Exon 2 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PNMA3	ENST00000593810.3	c.1091G>A	p.Gly364Glu	missense_variant	Exon 2 of 2	6	NM_013364.6	ENSP00000469445.1
PNMA3	ENST00000619635.1	c.1091G>A	p.Gly364Glu	missense_variant	Exon 2 of 3	1		ENSP00000480719.1
PNMA3	ENST00000424805.1	n.1091G>A		non_coding_transcript_exon_variant	Exon 2 of 3	5		ENSP00000390576.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 0.00000182 AC: 2 AN: 1097852 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 363298

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000331

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 24

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 16, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1091G>A (p.G364E) 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 1091, causing the glycine (G) at amino acid position 364 to be replaced by a glutamic acid (E). 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	0.080
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-1.1
CADD	Benign	1.2
DANN	Benign	0.39
DEOGEN2	Benign	0.023	.;T
FATHMM_MKL	Benign	0.0036	N
LIST_S2	Benign	0.50	T;T
M_CAP	Benign	0.00095	T
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.55	N;N
PrimateAI	Benign	0.38	T
Sift4G	Benign	0.66	T;T
Polyphen		0.0030	.;B
Vest4		0.095
MutPred		0.31		Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);
MVP		0.34
ClinPred		0.060	T
GERP RS		-4.0
Varity_R		0.17
gMVP		0.18

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-152226503;