X-153058205-C-T

Variant summary

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

The NM_013364.6(PNMA3):c.1150C>T(p.Arg384Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000306 in 1,210,520 control chromosomes in the GnomAD database, including 1 homozygotes. There are 100 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., 6 hem., cov: 24)
  • Exomes 𝑓: 0.00031 (1 hom. 94 hem.)
• Consequence: PNMA3 NM_013364.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.06

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=0.05381301).
• BS2: High Hemizygotes in GnomAd at 6 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PNMA3	NM_013364.6	c.1150C>T	p.Arg384Trp	missense_variant	2/2	ENST00000593810.3
PNMA3	NM_001282535.2	c.1150C>T	p.Arg384Trp	missense_variant	2/3
PNMA3	XR_938508.4	n.1425C>T		non_coding_transcript_exon_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PNMA3	ENST00000593810.3	c.1150C>T	p.Arg384Trp	missense_variant	2/2		NM_013364.6	P1
PNMA3	ENST00000619635.1	c.1150C>T	p.Arg384Trp	missense_variant	2/3	1
PNMA3	ENST00000424805.1	c.1150C>T	p.Arg384Trp	missense_variant, NMD_transcript_variant	2/3	5

Frequencies

GnomAD3 genomes AF: 0.000239 AC: 27 AN: 112798 Hom.: 0 Cov.: 24 AF XY: 0.000172 AC XY: 6 AN XY: 34958

Gnomad AFR AF: 0.0000322

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000279

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000280

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000413

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000182 AC: 33 AN: 181515 Hom.: 1 AF XY: 0.000165 AC XY: 11 AN XY: 66695

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000256

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000211

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000272

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000313 AC: 344 AN: 1097722 Hom.: 1 Cov.: 33 AF XY: 0.000259 AC XY: 94 AN XY: 363122

Gnomad4 AFR exome AF: 0.000114

Gnomad4 AMR exome AF: 0.000227

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000130

Gnomad4 FIN exome AF: 0.0000495

Gnomad4 NFE exome AF: 0.000374

Gnomad4 OTH exome AF: 0.000195

GnomAD4 genome AF: 0.000239 AC: 27 AN: 112798 Hom.: 0 Cov.: 24 AF XY: 0.000172 AC XY: 6 AN XY: 34958

Gnomad4 AFR AF: 0.0000322

Gnomad4 AMR AF: 0.000279

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000280

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000413

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000260 Hom.: 9

Bravo AF: 0.000178

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00134 AC: 9

ExAC AF: 0.000181 AC: 22

EpiCase AF: 0.000273

EpiControl AF: 0.000119

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

Dec 06, 2022

The c.1150C>T (p.R384W) alteration is located in exon 2 (coding exon 1) of the PNMA3 gene. This alteration results from a C to T substitution at nucleotide position 1150, causing the arginine (R) at amino acid position 384 to be replaced by a tryptophan (W). 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	0.14
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.86
Cadd	Benign	11
Dann	Benign	0.92
FATHMM_MKL	Benign	0.0016	N
LIST_S2	Benign	0.72	T;T
M_CAP	Benign	0.0030	T
MetaRNN	Benign	0.054	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.69	N;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.68	T
Sift4G	Uncertain	0.0030	D;D
Polyphen		0.0010	.;B
Vest4		0.11
MVP		0.35
ClinPred		0.019	T
GERP RS		-0.035
Varity_R		0.26
gMVP		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs144738062; hg19: chrX-152226562;