X-152990554-G-A

Variant names:

• chrX-152990554-G-A
• rs3810654
• NM_001184924.2:c.1045C>T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001184924.2(PNMA5):​c.1045C>T​(p.Arg349Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000194 in 1,200,090 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 83 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.000062 (0 hom., 3 hem., cov: 24)
  • Exomes 𝑓: 0.00021 (0 hom. 80 hem.)
• Consequence: PNMA5 NM_001184924.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.266

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.020149529).
• BS2: High Hemizygotes in GnomAd4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PNMA5	NM_001184924.2	c.1045C>T	p.Arg349Trp	missense_variant	Exon 4 of 4	ENST00000535214.6	NP_001171853.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PNMA5	ENST00000535214.6	c.1045C>T	p.Arg349Trp	missense_variant	Exon 4 of 4	3	NM_001184924.2	ENSP00000445775.1
PNMA5	ENST00000361887.5	c.1045C>T	p.Arg349Trp	missense_variant	Exon 2 of 2	1		ENSP00000354834.5
PNMA5	ENST00000439251.3	c.1045C>T	p.Arg349Trp	missense_variant	Exon 2 of 2	1		ENSP00000388850.1
PNMA5	ENST00000452693.5	c.1045C>T	p.Arg349Trp	missense_variant	Exon 3 of 3	2		ENSP00000392342.1

Frequencies

GnomAD3 genomes AF: 0.0000623 AC: 7 AN: 112331 Hom.: 0 Cov.: 24 AF XY: 0.0000869 AC XY: 3 AN XY: 34509

Gnomad AFR AF: 0.0000324

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000560

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000751

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000107 AC: 18 AN: 168399 Hom.: 0 AF XY: 0.000127 AC XY: 7 AN XY: 55215

Gnomad AFR exome AF: 0.0000770

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000379

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000144

Gnomad OTH exome AF: 0.000245

GnomAD4 exome AF: 0.000208 AC: 226 AN: 1087708 Hom.: 0 Cov.: 31 AF XY: 0.000225 AC XY: 80 AN XY: 355344

Gnomad4 AFR exome AF: 0.0000385

Gnomad4 AMR exome AF: 0.0000301

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00186

Gnomad4 SAS exome AF: 0.0000193

Gnomad4 FIN exome AF: 0.0000250

Gnomad4 NFE exome AF: 0.000186

Gnomad4 OTH exome AF: 0.000197

GnomAD4 genome AF: 0.0000623 AC: 7 AN: 112382 Hom.: 0 Cov.: 24 AF XY: 0.0000868 AC XY: 3 AN XY: 34570

Gnomad4 AFR AF: 0.0000323

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000561

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000752

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000218 Hom.: 2

Bravo AF: 0.0000453

ExAC AF: 0.000148 AC: 18

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1045C>T (p.R349W) alteration is located in exon 2 (coding exon 1) of the PNMA5 gene. This alteration results from a C to T substitution at nucleotide position 1045, causing the arginine (R) at amino acid position 349 to be replaced by a tryptophan (W). 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	0.12
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.94
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Benign	0.032	T;T;T;T
FATHMM_MKL	Benign	0.0080	N
LIST_S2	Benign	0.51	.;.;T;.
M_CAP	Benign	0.0026	T
MetaRNN	Benign	0.020	T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.55	N;N;N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.0	N;N;N;N
REVEL	Benign	0.042
Sift	Benign	0.18	T;T;T;T
Sift4G	Uncertain	0.056	T;T;T;T
Polyphen		0.017	B;B;B;B
Vest4		0.11
MutPred		0.17		Loss of methylation at R349 (P = 0.0052);Loss of methylation at R349 (P = 0.0052);Loss of methylation at R349 (P = 0.0052);Loss of methylation at R349 (P = 0.0052);
MVP		0.14
MPC		0.43
ClinPred		0.032	T
GERP RS		0.49
Varity_R		0.046
gMVP		0.20

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: rs3810654; hg19: chrX-152159098;