3-126988697-G-A

Position:

• chr3-126988697-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_032242.4(PLXNA1):​c.104G>A​(p.Gly35Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000703 in 1,422,358 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (no stars).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: PLXNA1 NM_032242.4 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 1.47

Genes affected

PLXNA1 (HGNC:9099): (plexin A1) Predicted to enable semaphorin receptor activity. Predicted to be involved in several processes, including generation of neurons; regulation of GTPase activity; and regulation of cell shape. Predicted to act upstream of or within dichotomous subdivision of terminal units involved in salivary gland branching; neuron projection morphogenesis; and regulation of smooth muscle cell migration. Located in cytosol and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PLXNA1. . Gene score misZ 3.4482 (greater than the threshold 3.09). Trascript score misZ 4.1522 (greater than threshold 3.09). GenCC has associacion of gene with Dworschak-Punetha neurodevelopmental syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.102990955).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLXNA1	NM_032242.4	c.104G>A	p.Gly35Glu	missense_variant	2/32	ENST00000393409.3	NP_115618.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLXNA1	ENST00000393409.3	c.104G>A	p.Gly35Glu	missense_variant	2/32	1	NM_032242.4	ENSP00000377061.2
PLXNA1	ENST00000684469.1	c.104G>A	p.Gly35Glu	missense_variant	2/2			ENSP00000507976.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 7.03e-7 AC: 1 AN: 1422358 Hom.: 0 Cov.: 33 AF XY: 0.00000142 AC XY: 1 AN XY: 702054

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: 9.17e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

PLXNA1-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 26, 2023

The PLXNA1 c.104G>A variant is predicted to result in the amino acid substitution p.Gly35Glu. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	11
DANN	Benign	0.36
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.0053	T
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.4	L
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.067
Sift	Benign	0.22	T
Sift4G	Benign	0.46	T
Polyphen		0.0	B
Vest4		0.15
MutPred		0.28		Gain of loop (P = 0.1069);
MVP		0.15
MPC		0.56
ClinPred		0.069	T
GERP RS		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.031
gMVP		0.56

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-126707540;