X-153058385-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_013364.6(PNMA3):c.1330G>A(p.Val444Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000334 in 1,210,826 control chromosomes in the GnomAD database, including 1 homozygotes. There are 154 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00047 (0 hom., 18 hem., cov: 25)
  • Exomes 𝑓: 0.00032 (1 hom. 136 hem.)
• Consequence: PNMA3 NM_013364.6 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.77

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007667154).
• BP6: Variant X-153058385-G-A is Benign according to our data. Variant chrX-153058385-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2368732.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAd at 18 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PNMA3	NM_013364.6	c.1330G>A	p.Val444Ile	missense_variant	2/2	ENST00000593810.3
PNMA3	NM_001282535.2	c.1305+25G>A		intron_variant
PNMA3	XR_938508.4	n.1605G>A		non_coding_transcript_exon_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PNMA3	ENST00000593810.3	c.1330G>A	p.Val444Ile	missense_variant	2/2		NM_013364.6	P1
PNMA3	ENST00000619635.1	c.1305+25G>A		intron_variant		1
PNMA3	ENST00000424805.1	c.1330G>A	p.Val444Ile	missense_variant, NMD_transcript_variant	2/3	5

Frequencies

GnomAD3 genomes AF: 0.000470 AC: 53 AN: 112683 Hom.: 0 Cov.: 25 AF XY: 0.000517 AC XY: 18 AN XY: 34821

Gnomad AFR AF: 0.0000323

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00186

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00144

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000413

Gnomad OTH AF: 0.000657

GnomAD3 exomes AF: 0.000480 AC: 88 AN: 183412 Hom.: 1 AF XY: 0.000604 AC XY: 41 AN XY: 67858

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000511

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00150

Gnomad NFE exome AF: 0.000598

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.000320 AC: 351 AN: 1098143 Hom.: 1 Cov.: 32 AF XY: 0.000374 AC XY: 136 AN XY: 363503

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000398

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00163

Gnomad4 NFE exome AF: 0.000300

Gnomad4 OTH exome AF: 0.000391

GnomAD4 genome AF: 0.000470 AC: 53 AN: 112683 Hom.: 0 Cov.: 25 AF XY: 0.000517 AC XY: 18 AN XY: 34821

Gnomad4 AFR AF: 0.0000323

Gnomad4 AMR AF: 0.00186

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00144

Gnomad4 NFE AF: 0.000413

Gnomad4 OTH AF: 0.000657

Alfa AF: 0.000516 Hom.: 21

Bravo AF: 0.000382

ExAC AF: 0.000486 AC: 59

EpiCase AF: 0.000436

EpiControl AF: 0.000652

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 14, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.93	T
BayesDel_noAF	Benign	-1.2
Cadd	Benign	0.26
Dann	Benign	0.31
DEOGEN2	Benign	0.011	T
FATHMM_MKL	Benign	0.00089	N
LIST_S2	Benign	0.15	T
M_CAP	Benign	0.0024	T
MetaRNN	Benign	0.0077	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.55	N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.36	T
Sift4G	Benign	0.24	T
Polyphen		0.0	B
Vest4		0.017
MVP		0.18
ClinPred		0.0029	T
GERP RS		-2.1
Varity_R		0.019
gMVP		0.37

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

Other links and lift over

dbSNP: rs202098633; hg19: chrX-152226742;