Genetic Variant PLXNA1:p.Gly29Ala (chr3-126988679-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_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. 15/22 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

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

Dworschak-Punetha neurodevelopmental syndrome
Inheritance: AR Classification: STRONG, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
complex neurodevelopmental disorder
Inheritance: AD Classification: LIMITED Submitted by: G2P

PLXNA1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07897872).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLXNA1	NM_032242.4 link	c.86G>C	p.Gly29Ala	missense_variant	Exon 2 of 32	ENST00000393409.3	NP_115618.3	Q9UIW2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLXNA1	ENST00000393409.3 link	c.86G>C	p.Gly29Ala	missense_variant	Exon 2 of 32	1	NM_032242.4	ENSP00000377061.2		Q9UIW2
PLXNA1	ENST00000684469.1 link	c.86G>C	p.Gly29Ala	missense_variant	Exon 2 of 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

African (AFR)

AF:

0.00

AC:

AN:

32858

American (AMR)

AF:

0.00

AC:

AN:

42014

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23784

East Asian (EAS)

AF:

0.00

AC:

AN:

39338

South Asian (SAS)

AF:

0.00

AC:

AN:

79856

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50782

Middle Eastern (MID)

AF:

0.000179

AC:

AN:

5594

European-Non Finnish (NFE)

AF:

9.15e-7

AC:

AN:

1093042

Other (OTH)

AF:

0.00

AC:

AN:

58852

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

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

Jul 20, 2023

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

(source)

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

PhyloP100

4.0

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

Mutation Taster

=85/15

polymorphism

(source)

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

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chr3-126988679-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over