Genetic Variant NM_032242.4:c.115C>A (chr3-126988708-C-A) – 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.115C>A(p.Pro39Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000254 in 1,573,274 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P39A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 34)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

PLXNA1
NM_032242.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.72

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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
complex neurodevelopmental disorder
Inheritance: AD Classification: LIMITED Submitted by: G2P

PLXNA1 links:

Genome browser will be placed here

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=0.085540235).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032242.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLXNA1	NM_032242.4	MANE Select	c.115C>A	p.Pro39Thr	missense	Exon 2 of 32	NP_115618.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLXNA1	ENST00000393409.3	TSL:1 MANE Select	c.115C>A	p.Pro39Thr	missense	Exon 2 of 32	ENSP00000377061.2	Q9UIW2
	PLXNA1	ENST00000684469.1		c.115C>A	p.Pro39Thr	missense	Exon 2 of 2	ENSP00000507976.1	A0A804HKL4

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000460

AC:

AN:

217520

AF XY:

0.00000863

show subpopulations

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000103

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000211

AC:

AN:

1421080

Hom.:

Cov.:

AF XY:

0.00000285

AC XY:

AN XY:

701040

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32968

American (AMR)

AF:

0.00

AC:

AN:

42474

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23466

East Asian (EAS)

AF:

0.00

AC:

AN:

39310

South Asian (SAS)

AF:

0.00

AC:

AN:

78664

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50668

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5586

European-Non Finnish (NFE)

AF:

0.00000275

AC:

AN:

1089314

Other (OTH)

AF:

0.00

AC:

AN:

58630

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41448

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68012

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

ExAC

AF:

0.00000826

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.63

CADD

Benign

(source)

DANN

Benign

0.42

DEOGEN2

Benign

0.14

Eigen

Benign

-0.57

Eigen_PC

Benign

-0.50

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.85

M_CAP

Benign

0.0048

MetaRNN

Benign

0.086

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.0

PhyloP100

2.7

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-1.1

REVEL

Benign

0.042

Sift

Benign

0.57

Sift4G

Benign

0.58

Polyphen

0.0010

Vest4

0.34

MutPred

0.30

Gain of phosphorylation at P39 (P = 0.0163)

MVP

0.20

MPC

0.48

ClinPred

0.047

GERP RS

3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.6

Varity_R

0.050

gMVP

0.52

Mutation Taster

=86/14

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over