chr10-80425892-A-C

Variant names:

• chr10-80425892-A-C
• rs1445702126
• NM_032333.5:c.297A>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_032333.5(PRXL2A):​c.297A>C​(p.Lys99Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000116 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: PRXL2A NM_032333.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.03

Genes affected

PRXL2A (HGNC:28651): (peroxiredoxin like 2A) Enables antioxidant activity. Involved in regulation of osteoclast differentiation. Located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.815

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRXL2A	NM_032333.5	c.297A>C	p.Lys99Asn	missense_variant	Exon 4 of 6	ENST00000606162.6	NP_115709.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRXL2A	ENST00000606162.6	c.297A>C	p.Lys99Asn	missense_variant	Exon 4 of 6	1	NM_032333.5	ENSP00000482445.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1461884 Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.0000153

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 28, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.297A>C (p.K99N) alteration is located in exon 4 (coding exon 3) of the FAM213A gene. This alteration results from a A to C substitution at nucleotide position 297, causing the lysine (K) at amino acid position 99 to be replaced by an asparagine (N). 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	Pathogenic	0.70
BayesDel_addAF	Benign	-0.059	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T;T;T;.;T;T
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.013
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.82	.;.;.;T;T;.
M_CAP	Benign	0.073	D
MetaRNN	Pathogenic	0.82	D;D;D;D;D;D
MetaSVM	Benign	-0.53	T
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-4.1	D;.;.;D;D;D
REVEL	Benign	0.29
Sift	Uncertain	0.012	D;.;.;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D;D;D
Polyphen		1.0	D;D;D;.;D;D
Vest4		0.75
MutPred		0.43		Loss of ubiquitination at K99 (P = 0.0107);Loss of ubiquitination at K99 (P = 0.0107);Loss of ubiquitination at K99 (P = 0.0107);.;Loss of ubiquitination at K99 (P = 0.0107);Loss of ubiquitination at K99 (P = 0.0107);
MVP		0.62
MPC		0.95
ClinPred		0.99	D
GERP RS		-0.86
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.49
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1445702126; hg19: chr10-82185648;