Genetic Variant PNMA3:p.Arg385His (chrX-153058209-G-A) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_013364.6(PNMA3):c.1154G>A(p.Arg385His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000112 in 1,210,750 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 50 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 2 hem., cov: 24)

Exomes 𝑓: 0.00012 ( 0 hom. 48 hem. )

Consequence

PNMA3
NM_013364.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.24

Publications

0 publications found

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 was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.08159965).

BS2

High Hemizygotes in GnomAd4 at 2 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013364.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNMA3	NM_013364.6	MANE Select	c.1154G>A	p.Arg385His	missense	Exon 2 of 2	NP_037496.4	Q9UL41-1
	PNMA3	NM_001282535.2		c.1154G>A	p.Arg385His	missense	Exon 2 of 3	NP_001269464.1	Q9UL41-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PNMA3	ENST00000593810.3	TSL:6 MANE Select	c.1154G>A	p.Arg385His	missense	Exon 2 of 2	ENSP00000469445.1	Q9UL41-1
PNMA3	ENST00000619635.1	TSL:1	c.1154G>A	p.Arg385His	missense	Exon 2 of 3	ENSP00000480719.1	Q9UL41-2
PNMA3	ENST00000424805.1	TSL:5	n.1154G>A		non_coding_transcript_exon	Exon 2 of 3	ENSP00000390576.1	Q9UL41-1

Frequencies

GnomAD3 genomes

AF:

0.0000266

AC:

AN:

112923

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000643

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:

0.0000187

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000605

AC:

AN:

181708

AF XY:

0.0000449

show subpopulations

Gnomad AFR exome

AF:

0.0000777

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000724

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000111

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000121

AC:

133

AN:

1097827

Hom.:

Cov.:

AF XY:

0.000132

AC XY:

AN XY:

363233

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26401

American (AMR)

AF:

0.00

AC:

AN:

35194

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19358

East Asian (EAS)

AF:

0.0000662

AC:

AN:

30203

South Asian (SAS)

AF:

0.000148

AC:

AN:

54086

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40425

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4130

European-Non Finnish (NFE)

AF:

0.000140

AC:

118

AN:

841954

Other (OTH)

AF:

0.000109

AC:

AN:

46076

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000266

AC:

AN:

112923

Hom.:

Cov.:

AF XY:

0.0000570

AC XY:

AN XY:

35067

show subpopulations

African (AFR)

AF:

0.0000643

AC:

AN:

31097

American (AMR)

AF:

0.00

AC:

AN:

10774

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2660

East Asian (EAS)

AF:

0.00

AC:

AN:

3579

South Asian (SAS)

AF:

0.00

AC:

AN:

2746

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6265

Middle Eastern (MID)

AF:

0.00

AC:

AN:

240

European-Non Finnish (NFE)

AF:

0.0000187

AC:

AN:

53347

Other (OTH)

AF:

0.00

AC:

AN:

1527

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000824

Hom.:

Bravo

AF:

0.0000264

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.77

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.022

FATHMM_MKL

Benign

0.017

LIST_S2

Benign

0.58

M_CAP

Benign

0.0038

MetaRNN

Benign

0.082

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.81

PhyloP100

1.2

PrimateAI

Uncertain

0.63

Sift4G

Uncertain

0.032

Polyphen

0.99

Vest4

0.12

MVP

0.28

ClinPred

0.13

GERP RS

1.9

Varity_R

0.070

gMVP

0.34

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over