chr3-126988626-C-T

Variant names:

• chr3-126988626-C-T
• rs373455804
• NM_032242.4:c.33C>T

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.33C>T​(p.Leu11Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00041 in 1,569,538 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00043 (1 hom.)
• Consequence: PLXNA1 NM_032242.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -0.549
• 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: Labcorp Genetics (formerly Invitae), G2P, 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=-0.88).
• BP6: Variant 3-126988626-C-T is Benign according to our data. Variant chr3-126988626-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2045806.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.549 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000256 (39/152314) while in subpopulation NFE AF = 0.0005 (34/68006). AF 95% confidence interval is 0.000368. 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.

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.33C>T	p.Leu11Leu	synonymous	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.33C>T	p.Leu11Leu	synonymous	Exon 2 of 32	ENSP00000377061.2	Q9UIW2
	PLXNA1	ENST00000684469.1		c.33C>T	p.Leu11Leu	synonymous	Exon 2 of 2	ENSP00000507976.1	A0A804HKL4

Frequencies

GnomAD3 genomes AF: 0.000256 AC: 39 AN: 152198 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000500

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000318 AC: 58 AN: 182628 AF XY: 0.000384

Gnomad AFR exome AF: 0.0000820

Gnomad AMR exome AF: 0.000149

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000525

Gnomad OTH exome AF: 0.000658

GnomAD4 exome AF: 0.000427 AC: 605 AN: 1417224 Hom.: 1 Cov.: 32 AF XY: 0.000423 AC XY: 296 AN XY: 700548

African (AFR) AF: 0.000154 AC: 5 AN: 32552

American (AMR) AF: 0.000224 AC: 9 AN: 40180

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23254

East Asian (EAS) AF: 0.00 AC: 0 AN: 39120

South Asian (SAS) AF: 0.000230 AC: 18 AN: 78302

European-Finnish (FIN) AF: 0.000162 AC: 8 AN: 49294

Middle Eastern (MID) AF: 0.00217 AC: 12 AN: 5542

European-Non Finnish (NFE) AF: 0.000490 AC: 534 AN: 1090454

Other (OTH) AF: 0.000325 AC: 19 AN: 58526

GnomAD4 genome AF: 0.000256 AC: 39 AN: 152314 Hom.: 0 Cov.: 34 AF XY: 0.000175 AC XY: 13 AN XY: 74478

African (AFR) AF: 0.0000240 AC: 1 AN: 41584

American (AMR) AF: 0.000131 AC: 2 AN: 15312

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10610

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

European-Non Finnish (NFE) AF: 0.000500 AC: 34 AN: 68006

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000475 Hom.: 0

Bravo AF: 0.000283

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	PLXNA1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.33
DANN	Benign	0.41
PhyloP100		-0.55
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=297/3	polymorphism

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: rs373455804; hg19: chr3-126707469;