chr1-208027314-C-T

Position:

• chr1-208027314-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_025179.4(PLXNA2):​c.5614G>A​(p.Glu1872Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,090 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PLXNA2 NM_025179.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.62

Genes affected

PLXNA2 (HGNC:9100): (plexin A2) This gene encodes a member of the plexin-A family of semaphorin co-receptors. Semaphorins are a large family of secreted or membrane-bound proteins that mediate repulsive effects on axon pathfinding during nervous system development. A subset of semaphorins are recognized by plexin-A/neuropilin transmembrane receptor complexes, triggering a cellular signal transduction cascade that leads to axon repulsion. This plexin-A family member is thought to transduce signals from semaphorin-3A and -3C. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35796708).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLXNA2	NM_025179.4	c.5614G>A	p.Glu1872Lys	missense_variant	32/32	ENST00000367033.4
PLXNA2	XM_005273164.4	c.5854G>A	p.Glu1952Lys	missense_variant	33/33

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLXNA2	ENST00000367033.4	c.5614G>A	p.Glu1872Lys	missense_variant	32/32	1	NM_025179.4	P1
PLXNA2	ENST00000483048.1	n.1650G>A		non_coding_transcript_exon_variant	3/3	1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461090 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726890

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 22, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with PLXNA2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1872 of the PLXNA2 protein (p.Glu1872Lys). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.028	T
BayesDel_noAF	Benign	-0.28
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.36	T
MetaSVM	Benign	-0.78	T
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.19
Sift	Benign	0.078	T
Sift4G	Benign	0.27	T
Polyphen		0.51	P
Vest4		0.53
MutPred		0.39		Gain of MoRF binding (P = 0.006);
MVP		0.18
MPC		0.81
ClinPred		0.97	D
GERP RS		5.2
Varity_R		0.55
gMVP		0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1571835947; hg19: chr1-208200659;