chr1-208027304-C-A

Variant names:

• chr1-208027304-C-A
• rs573661376
• NM_025179.4:c.5624G>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_025179.4(PLXNA2):​c.5624G>T​(p.Arg1875Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,212 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1875Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PLXNA2 NM_025179.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.03

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLXNA2	NM_025179.4	c.5624G>T	p.Arg1875Leu	missense_variant	Exon 32 of 32	ENST00000367033.4	NP_079455.3
PLXNA2	XM_005273164.4	c.5864G>T	p.Arg1955Leu	missense_variant	Exon 33 of 33		XP_005273221.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLXNA2	ENST00000367033.4	c.5624G>T	p.Arg1875Leu	missense_variant	Exon 32 of 32	1	NM_025179.4	ENSP00000356000.3
PLXNA2	ENST00000483048.1	n.1660G>T		non_coding_transcript_exon_variant	Exon 3 of 3	1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249120 Hom.: 0 AF XY: 0.00000741 AC XY: 1 AN XY: 134890

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461212 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726962

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: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.032	D
MetaRNN	Uncertain	0.42	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.6	M
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Benign	0.14
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.013	D
Polyphen		0.77	P
Vest4		0.53
MutPred		0.36		Loss of MoRF binding (P = 0.0191);
MVP		0.20
MPC		1.7
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.32
gMVP		0.70

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: rs573661376; hg19: chr1-208200649;