Genetic Variant PNMA5:p.Gly428Ala (chrX-152990316-C-G) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001184924.2(PNMA5):c.1283G>C(p.Gly428Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000868 in 1,036,497 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. 14/20 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: 0.0000087 ( 0 hom. 3 hem. )

Consequence

PNMA5
NM_001184924.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -3.65

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.020982146).

BS2

High Hemizygotes in GnomAdExome4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PNMA5	NM_001184924.2 link	c.1283G>C	p.Gly428Ala	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.1283G>C	p.Gly428Ala	missense_variant	Exon 4 of 4	3	NM_001184924.2	ENSP00000445775.1	Q96PV4
PNMA5	ENST00000361887.5 link	c.1283G>C	p.Gly428Ala	missense_variant	Exon 2 of 2	1		ENSP00000354834.5	Q96PV4
PNMA5	ENST00000439251.3 link	c.1283G>C	p.Gly428Ala	missense_variant	Exon 2 of 2	1		ENSP00000388850.1	Q96PV4
PNMA5	ENST00000452693.5 link	c.1283G>C	p.Gly428Ala	missense_variant	Exon 3 of 3	2		ENSP00000392342.1	Q96PV4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000640

AC:

AN:

125038

Hom.:

AF XY:

0.0000504

AC XY:

AN XY:

39684

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000535

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000868

AC:

AN:

1036497

Hom.:

Cov.:

AF XY:

0.00000897

AC XY:

AN XY:

334289

show subpopulations

Gnomad4 AFR exome

AF:

0.0000420

Gnomad4 AMR exome

AF:

0.000361

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000340

ExAC

AF:

0.0000503

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 14, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1283G>C (p.G428A) alteration is located in exon 2 (coding exon 1) of the PNMA5 gene. This alteration results from a G to C substitution at nucleotide position 1283, causing the glycine (G) at amino acid position 428 to be replaced by an alanine (A). 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

0.063

BayesDel_addAF

Benign

-0.84

BayesDel_noAF

Benign

-1.1

CADD

Benign

0.0020

DANN

Benign

0.46

DEOGEN2

Benign

0.0052

T;T;T;T

FATHMM_MKL

Benign

0.00067

LIST_S2

Benign

0.26

.;.;T;.

M_CAP

Benign

0.0018

MetaRNN

Benign

0.021

T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-0.20

N;N;N;N

PrimateAI

Benign

0.26

PROVEAN

Benign

0.88

N;N;N;N

REVEL

Benign

0.0060

Sift

Benign

1.0

T;T;T;T

Sift4G

Benign

0.34

T;T;T;T

Polyphen

0.0

B;B;B;B

Vest4

0.061

MutPred

0.25

Gain of helix (P = 0.0199);Gain of helix (P = 0.0199);Gain of helix (P = 0.0199);Gain of helix (P = 0.0199);

MVP

0.12

MPC

0.10

ClinPred

0.021

GERP RS

-5.5

Varity_R

0.028

gMVP

0.21

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