X-152990296-C-T

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001184924.2(PNMA5):c.1303G>A(p.Ala435Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000089 in 112,399 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A435V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 24)

Exomes 𝑓: 0.0000039 ( 0 hom. 2 hem. )

Failed GnomAD Quality Control

Consequence

PNMA5
NM_001184924.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.906

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 -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.021935433).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PNMA5	NM_001184924.2 link	c.1303G>A	p.Ala435Thr	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.1303G>A	p.Ala435Thr	missense_variant	Exon 4 of 4	3	NM_001184924.2	ENSP00000445775.1	Q96PV4
PNMA5	ENST00000361887.5 link	c.1303G>A	p.Ala435Thr	missense_variant	Exon 2 of 2	1		ENSP00000354834.5	Q96PV4
PNMA5	ENST00000439251.3 link	c.1303G>A	p.Ala435Thr	missense_variant	Exon 2 of 2	1		ENSP00000388850.1	Q96PV4
PNMA5	ENST00000452693.5 link	c.1303G>A	p.Ala435Thr	missense_variant	Exon 3 of 3	2		ENSP00000392342.1	Q96PV4

Frequencies

GnomAD3 genomes

AF:

0.00000890

AC:

AN:

112399

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34541

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000933

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000851

AC:

AN:

117474

Hom.:

AF XY:

0.00

AC XY:

AN XY:

37466

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000774

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

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000393

AC:

AN:

1017746

Hom.:

Cov.:

AF XY:

0.00000618

AC XY:

AN XY:

323656

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000203

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

AF:

0.00000890

AC:

AN:

112399

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34541

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000933

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 19, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1303G>A (p.A435T) 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 1303, causing the alanine (A) at amino acid position 435 to be replaced by a threonine (T). 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

0.076

BayesDel_addAF

Benign

-0.75

BayesDel_noAF

Benign

-1.1

CADD

Benign

0.028

DANN

Benign

0.67

DEOGEN2

Benign

0.0080

T;T;T;T

FATHMM_MKL

Benign

0.0013

LIST_S2

Benign

0.31

.;.;T;.

M_CAP

Benign

0.0019

MetaRNN

Benign

0.022

T;T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.0

N;N;N;N

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.47

N;N;N;N

REVEL

Benign

0.0030

Sift

Benign

1.0

T;T;T;T

Sift4G

Benign

0.82

T;T;T;T

Polyphen

0.0010

B;B;B;B

Vest4

0.047

MutPred

0.18

Gain of phosphorylation at A435 (P = 0.0412);Gain of phosphorylation at A435 (P = 0.0412);Gain of phosphorylation at A435 (P = 0.0412);Gain of phosphorylation at A435 (P = 0.0412);

MVP

0.17

MPC

0.089

ClinPred

0.015

GERP RS

-4.8

Varity_R

0.027

gMVP

0.13

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