3-126988659-G-A

Variant names:

• chr3-126988659-G-A
• rs375921132
• NM_032242.4:c.66G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_032242.4(PLXNA1):​c.66G>A​(p.Pro22Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000492 in 1,578,662 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00053 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00049 (2 hom.)
• Consequence: PLXNA1 NM_032242.4 synonymous
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.836
• Publications: 0 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 3-126988659-G-A is Benign according to our data. Variant chr3-126988659-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3052460.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=-0.836 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000525 (80/152318) while in subpopulation NFE AF = 0.000441 (30/68018). AF 95% confidence interval is 0.000317. There are 0 homozygotes in GnomAd4. There are 38 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLXNA1	NM_032242.4	c.66G>A	p.Pro22Pro	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.66G>A	p.Pro22Pro	synonymous_variant	Exon 2 of 32	1	NM_032242.4	ENSP00000377061.2
PLXNA1	ENST00000684469.1	c.66G>A	p.Pro22Pro	synonymous_variant	Exon 2 of 2			ENSP00000507976.1

Frequencies

GnomAD3 genomes AF: 0.000526 AC: 80 AN: 152200 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00691

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000532 AC: 115 AN: 215972 AF XY: 0.000556

Gnomad AFR exome AF: 0.000479

Gnomad AMR exome AF: 0.000227

Gnomad ASJ exome AF: 0.00534

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000586

Gnomad OTH exome AF: 0.000568

GnomAD4 exome AF: 0.000488 AC: 696 AN: 1426344 Hom.: 2 Cov.: 33 AF XY: 0.000483 AC XY: 341 AN XY: 705694

African (AFR) AF: 0.000367 AC: 12 AN: 32734

American (AMR) AF: 0.000243 AC: 10 AN: 41230

Ashkenazi Jewish (ASJ) AF: 0.00541 AC: 129 AN: 23854

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39350

South Asian (SAS) AF: 0.000175 AC: 14 AN: 80180

European-Finnish (FIN) AF: 0.0000395 AC: 2 AN: 50650

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5596

European-Non Finnish (NFE) AF: 0.000462 AC: 505 AN: 1093960

Other (OTH) AF: 0.000391 AC: 23 AN: 58790

GnomAD4 genome AF: 0.000525 AC: 80 AN: 152318 Hom.: 0 Cov.: 34 AF XY: 0.000510 AC XY: 38 AN XY: 74460

African (AFR) AF: 0.000409 AC: 17 AN: 41578

American (AMR) AF: 0.000327 AC: 5 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00691 AC: 24 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

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

European-Non Finnish (NFE) AF: 0.000441 AC: 30 AN: 68018

Other (OTH) AF: 0.00142 AC: 3 AN: 2110

Alfa AF: 0.00105 Hom.: 0

Bravo AF: 0.000586

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

PLXNA1-related disorder Benign:1

Aug 28, 2019

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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.7
DANN	Benign	0.51
PhyloP100		-0.84
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs375921132; hg19: chr3-126707502;