Variant X-153058263-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_013364.6(PNMA3):c.1208G>C(p.Arg403Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,210,987 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 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 0.0000089 ( 0 hom., 1 hem., cov: 25)

Exomes 𝑓: 0.0000018 ( 0 hom. 2 hem. )

Consequence

PNMA3
NM_013364.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.136

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 -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07934263).

BS2

High Hemizygotes in GnomAdExome4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
PNMA3	NM_013364.6 linkuse as main transcript	c.1208G>C	p.Arg403Pro	missense_variant	2/2	ENST00000593810.3
PNMA3	NM_001282535.2 linkuse as main transcript	c.1208G>C	p.Arg403Pro	missense_variant	2/3
PNMA3	XR_938508.4 linkuse as main transcript	n.1483G>C		non_coding_transcript_exon_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PNMA3	ENST00000593810.3 linkuse as main transcript	c.1208G>C	p.Arg403Pro	missense_variant	2/2		NM_013364.6	P1	Q9UL41-1
PNMA3	ENST00000619635.1 linkuse as main transcript	c.1208G>C	p.Arg403Pro	missense_variant	2/3	1			Q9UL41-2
PNMA3	ENST00000424805.1 linkuse as main transcript	c.1208G>C	p.Arg403Pro	missense_variant, NMD_transcript_variant	2/3	5			Q9UL41-1

Frequencies

GnomAD3 genomes

AF:

0.00000886

AC:

AN:

112828

Hom.:

Cov.:

AF XY:

0.0000286

AC XY:

AN XY:

34976

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000546

AC:

AN:

183023

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

67679

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000123

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000182

AC:

AN:

1098159

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

363519

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000238

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000886

AC:

AN:

112828

Hom.:

Cov.:

AF XY:

0.0000286

AC XY:

AN XY:

34976

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000188

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 15, 2021

The c.1208G>C (p.R403P) alteration is located in exon 2 (coding exon 1) of the PNMA3 gene. This alteration results from a G to C substitution at nucleotide position 1208, causing the arginine (R) at amino acid position 403 to be replaced by a proline (P). 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

0.089

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.96

CADD

Benign

DANN

Benign

0.43

FATHMM_MKL

Benign

0.0078

LIST_S2

Benign

0.52

T;T

M_CAP

Benign

0.0019

MetaRNN

Benign

0.079

T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.69

N;N

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Uncertain

0.53

Sift4G

Uncertain

0.012

D;T

Polyphen

0.0

.;B

Vest4

0.095

MutPred

0.37

Gain of glycosylation at R403 (P = 0.0099);Gain of glycosylation at R403 (P = 0.0099);

MVP

0.13

ClinPred

0.014

GERP RS

-0.15

Varity_R

0.29

gMVP

0.43

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

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