Variant 3-126988679-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_032242.4(PLXNA1):c.86G>C(p.Gly29Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000014 in 1,426,120 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PLXNA1
NM_032242.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.02

Variant links:

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]

PLXNA1 links:

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ACMG classification

Classification made for transcript

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=0.07897872).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLXNA1	NM_032242.4 linkuse as main transcript	c.86G>C	p.Gly29Ala	missense_variant	2/32	ENST00000393409.3	NP_115618.3	Q9UIW2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLXNA1	ENST00000393409.3 linkuse as main transcript	c.86G>C	p.Gly29Ala	missense_variant	2/32	1	NM_032242.4	ENSP00000377061.2		Q9UIW2
PLXNA1	ENST00000684469.1 linkuse as main transcript	c.86G>C	p.Gly29Ala	missense_variant	2/2			ENSP00000507976.1		A0A804HKL4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000140

AC:

AN:

1426120

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

705052

show subpopulations

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:

9.15e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

PLXNA1-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 20, 2023

The PLXNA1 c.86G>C variant is predicted to result in the amino acid substitution p.Gly29Ala. 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

0.064

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.71

CADD

Benign

8.5

DANN

Benign

0.088

DEOGEN2

Benign

0.093

Eigen

Benign

-0.92

Eigen_PC

Benign

-0.87

FATHMM_MKL

Benign

0.67

LIST_S2

Benign

0.46

M_CAP

Benign

0.010

MetaRNN

Benign

0.079

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.0

PrimateAI

Benign

0.43

PROVEAN

Benign

0.19

REVEL

Benign

0.024

Sift

Benign

1.0

Sift4G

Benign

0.95

Polyphen

0.0

Vest4

0.14

MutPred

0.36

Loss of catalytic residue at A28 (P = 0.0779);

MVP

0.22

MPC

0.46

ClinPred

0.049

GERP RS

1.9

Varity_R

0.042

gMVP

0.60

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over