3-126988659-G-C

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_032242.4(PLXNA1):​c.66G>C​(p.Pro22Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000014 in 1,426,346 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. P22P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PLXNA1 NM_032242.4 synonymous
• Clinical Significance: Not reported in ClinVar
• 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP7: Synonymous conserved (PhyloP=-0.836 with no splicing effect.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1426346 Hom.: 0 Cov.: 33 AF XY: 0.00000142 AC XY: 1 AN XY: 705696

African (AFR) AF: 0.00 AC: 0 AN: 32734

American (AMR) AF: 0.00 AC: 0 AN: 41230

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23854

East Asian (EAS) AF: 0.00 AC: 0 AN: 39350

South Asian (SAS) AF: 0.00 AC: 0 AN: 80180

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50650

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

European-Non Finnish (NFE) AF: 0.00000183 AC: 2 AN: 1093962

Other (OTH) AF: 0.00 AC: 0 AN: 58790

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.42
DANN	Benign	0.35
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;