NM_032242.4:c.15G>A

Variant names:

• chr3-126988608-G-A
• rs552827234
• NM_032242.4:c.15G>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS1

The NM_032242.4(PLXNA1):​c.15G>A​(p.Pro5Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000559 in 1,538,822 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. P5P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000046 (0 hom.)
• Consequence: PLXNA1 NM_032242.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -2.30
• Publications: 1 publications found

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

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 3-126988608-G-A is Benign according to our data. Variant chr3-126988608-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3045514.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-2.3 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000144 (22/152364) while in subpopulation EAS AF = 0.00193 (10/5180). AF 95% confidence interval is 0.00105. There are 0 homozygotes in GnomAd4. There are 13 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLXNA1	NM_032242.4	c.15G>A	p.Pro5Pro	synonymous_variant	Exon 2 of 32	ENST00000393409.3	NP_115618.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLXNA1	ENST00000393409.3	c.15G>A	p.Pro5Pro	synonymous_variant	Exon 2 of 32	1	NM_032242.4	ENSP00000377061.2
PLXNA1	ENST00000684469.1	c.15G>A	p.Pro5Pro	synonymous_variant	Exon 2 of 2			ENSP00000507976.1

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152246 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00193

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: 0.000157 AC: 26 AN: 165134 AF XY: 0.000157

Gnomad AFR exome AF: 0.0000921

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00176

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000462 AC: 64 AN: 1386458 Hom.: 0 Cov.: 32 AF XY: 0.0000410 AC XY: 28 AN XY: 682590

African (AFR) AF: 0.0000948 AC: 3 AN: 31634

American (AMR) AF: 0.00 AC: 0 AN: 35178

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22008

East Asian (EAS) AF: 0.000765 AC: 29 AN: 37896

South Asian (SAS) AF: 0.0000403 AC: 3 AN: 74362

European-Finnish (FIN) AF: 0.0000218 AC: 1 AN: 45894

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5398

European-Non Finnish (NFE) AF: 0.0000167 AC: 18 AN: 1076786

Other (OTH) AF: 0.000175 AC: 10 AN: 57302

GnomAD4 genome AF: 0.000144 AC: 22 AN: 152364 Hom.: 0 Cov.: 34 AF XY: 0.000175 AC XY: 13 AN XY: 74498

African (AFR) AF: 0.000264 AC: 11 AN: 41592

American (AMR) AF: 0.00 AC: 0 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00193 AC: 10 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000117

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

PLXNA1-related disorder Benign:1

Dec 09, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Feb 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.12
DANN	Benign	0.56
PhyloP100		-2.3

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

Other links and lift over

dbSNP: rs552827234; hg19: chr3-126707451;