X-152990296-C-T

Variant names:

• chrX-152990296-C-T
• rs1556924131
• NM_001184924.2:c.1303G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_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. 15/21 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.906
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.021935433).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001184924.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNMA5	NM_001184924.2	MANE Select	c.1303G>A	p.Ala435Thr	missense	Exon 4 of 4	NP_001171853.1	Q96PV4
	PNMA5	NM_001103150.1		c.1303G>A	p.Ala435Thr	missense	Exon 2 of 2	NP_001096620.1	Q96PV4
	PNMA5	NM_001103151.1		c.1303G>A	p.Ala435Thr	missense	Exon 3 of 3	NP_001096621.1	Q96PV4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNMA5	ENST00000535214.6	TSL:3 MANE Select	c.1303G>A	p.Ala435Thr	missense	Exon 4 of 4	ENSP00000445775.1	Q96PV4
	PNMA5	ENST00000361887.5	TSL:1	c.1303G>A	p.Ala435Thr	missense	Exon 2 of 2	ENSP00000354834.5	Q96PV4
	PNMA5	ENST00000439251.3	TSL:1	c.1303G>A	p.Ala435Thr	missense	Exon 2 of 2	ENSP00000388850.1	Q96PV4

Frequencies

GnomAD3 genomes AF: 0.00000890 AC: 1 AN: 112399 Hom.: 0 Cov.: 24

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

GnomAD2 exomes AF: 0.00000851 AC: 1 AN: 117474 AF XY: 0.00

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 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: 4 AN: 1017746 Hom.: 0 Cov.: 30 AF XY: 0.00000618 AC XY: 2 AN XY: 323656

African (AFR) AF: 0.00 AC: 0 AN: 23202

American (AMR) AF: 0.000203 AC: 4 AN: 19751

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14509

East Asian (EAS) AF: 0.00 AC: 0 AN: 28299

South Asian (SAS) AF: 0.00 AC: 0 AN: 40529

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37589

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3759

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 807670

Other (OTH) AF: 0.00 AC: 0 AN: 42438

GnomAD4 genome AF: 0.00000890 AC: 1 AN: 112399 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 34541

African (AFR) AF: 0.00 AC: 0 AN: 30942

American (AMR) AF: 0.0000933 AC: 1 AN: 10722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2646

East Asian (EAS) AF: 0.00 AC: 0 AN: 3564

South Asian (SAS) AF: 0.00 AC: 0 AN: 2709

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6208

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53186

Other (OTH) AF: 0.00 AC: 0 AN: 1501

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-1.1
CADD	Benign	0.028
DANN	Benign	0.67
DEOGEN2	Benign	0.0080	T
FATHMM_MKL	Benign	0.0013	N
LIST_S2	Benign	0.31	T
M_CAP	Benign	0.0019	T
MetaRNN	Benign	0.022	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.91
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.47	N
REVEL	Benign	0.0030
Sift	Benign	1.0	T
Sift4G	Benign	0.82	T
Polyphen		0.0010	B
Vest4		0.047
MutPred		0.18		Gain of phosphorylation at A435 (P = 0.0412)
MVP		0.17
MPC		0.089
ClinPred		0.015	T
GERP RS		-4.8
Varity_R		0.027
gMVP		0.13
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs1556924131; hg19: chrX-152158840;