Genetic Variant PNMA5:p.Gly438Arg (chrX-152990287-C-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

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

The NM_001184924.2(PNMA5):c.1312G>A(p.Gly438Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000382 in 1,126,930 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 12 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000036 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.000038 ( 0 hom. 12 hem. )

Consequence

PNMA5
NM_001184924.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.435

Variant links:

Genes affected

PNMA5 (HGNC:18743): (PNMA family member 5) This gene encodes a member of the paraneoplastic Ma antigen protein family. These proteins have been implicated in the development of paraneoplastic disorders resulting from an immune response directed against them. Paraneoplastic disorders are the result of an abnormal immune response to a tumor. Multiple alternatively spliced variants, encoding the same protein, have been identified. [provided by RefSeq, Oct 2011]

PNMA5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.09318352).

BS2

High Hemizygotes in GnomAdExome4 at 12 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PNMA5	NM_001184924.2 link	c.1312G>A	p.Gly438Arg	missense_variant	Exon 4 of 4	ENST00000535214.6	NP_001171853.1	Q96PV4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PNMA5	ENST00000535214.6 link	c.1312G>A	p.Gly438Arg	missense_variant	Exon 4 of 4	3	NM_001184924.2	ENSP00000445775.1	Q96PV4
PNMA5	ENST00000361887.5 link	c.1312G>A	p.Gly438Arg	missense_variant	Exon 2 of 2	1		ENSP00000354834.5	Q96PV4
PNMA5	ENST00000439251.3 link	c.1312G>A	p.Gly438Arg	missense_variant	Exon 2 of 2	1		ENSP00000388850.1	Q96PV4
PNMA5	ENST00000452693.5 link	c.1312G>A	p.Gly438Arg	missense_variant	Exon 3 of 3	2		ENSP00000392342.1	Q96PV4

Frequencies

GnomAD3 genomes

AF:

0.0000356

AC:

AN:

112388

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34550

show subpopulations

Gnomad AFR

AF:

0.0000646

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:

0.0000376

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000171

AC:

AN:

116653

Hom.:

AF XY:

0.0000268

AC XY:

AN XY:

37331

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:

0.0000346

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000384

AC:

AN:

1014486

Hom.:

Cov.:

AF XY:

0.0000373

AC XY:

AN XY:

322092

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:

0.0000484

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000356

AC:

AN:

112444

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34616

show subpopulations

Gnomad4 AFR

AF:

0.0000645

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:

0.0000376

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ExAC

AF:

0.00000858

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1312G>A (p.G438R) alteration is located in exon 2 (coding exon 1) of the PNMA5 gene. This alteration results from a G to A substitution at nucleotide position 1312, causing the glycine (G) at amino acid position 438 to be replaced by an arginine (R). 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

Uncertain

0.35

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.89

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.024

T;T;T;T

FATHMM_MKL

Benign

0.063

LIST_S2

Benign

0.52

.;.;T;.

M_CAP

Benign

0.0047

MetaRNN

Benign

0.093

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.69

N;N;N;N

PrimateAI

Benign

0.38

PROVEAN

Benign

-1.3

N;N;N;N

REVEL

Benign

0.080

Sift

Benign

0.21

T;T;T;T

Sift4G

Benign

0.20

T;T;T;T

Polyphen

1.0

D;D;D;D

Vest4

0.23

MutPred

0.41

Gain of MoRF binding (P = 0.013);Gain of MoRF binding (P = 0.013);Gain of MoRF binding (P = 0.013);Gain of MoRF binding (P = 0.013);

MVP

0.17

MPC

0.52

ClinPred

0.55

GERP RS

2.0

Varity_R

0.061

gMVP

0.29

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