rs72957093

Variant names:

• chr3-126988607-C-T
• rs72957093
• NM_032242.4:c.14C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS1

The NM_032242.4(PLXNA1):​c.14C>T​(p.Pro5Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000277 in 1,536,156 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Synonymous variant affecting the same amino acid position (i.e. P5P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00016 (1 hom.)
• Consequence: PLXNA1 NM_032242.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.729
• Publications: 3 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0029713213).
• BP6: Variant 3-126988607-C-T is Benign according to our data. Variant chr3-126988607-C-T is described in ClinVar as [Benign]. Clinvar id is 2866220.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00131 (200/152382) while in subpopulation AFR AF = 0.00462 (192/41590). AF 95% confidence interval is 0.00408. There are 0 homozygotes in GnomAd4. There are 99 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.14C>T	p.Pro5Leu	missense_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.14C>T	p.Pro5Leu	missense_variant	Exon 2 of 32	1	NM_032242.4	ENSP00000377061.2
PLXNA1	ENST00000684469.1	c.14C>T	p.Pro5Leu	missense_variant	Exon 2 of 2			ENSP00000507976.1

Frequencies

GnomAD3 genomes AF: 0.00128 AC: 195 AN: 152264 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00451

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

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: 0.000956

GnomAD2 exomes AF: 0.000396 AC: 64 AN: 161422 AF XY: 0.000287

Gnomad AFR exome AF: 0.00471

Gnomad AMR exome AF: 0.000407

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000420

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000163 AC: 226 AN: 1383774 Hom.: 1 Cov.: 32 AF XY: 0.000159 AC XY: 108 AN XY: 681114

African (AFR) AF: 0.00431 AC: 136 AN: 31560

American (AMR) AF: 0.000317 AC: 11 AN: 34680

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21916

East Asian (EAS) AF: 0.0000530 AC: 2 AN: 37722

South Asian (SAS) AF: 0.000108 AC: 8 AN: 74054

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5378

European-Non Finnish (NFE) AF: 0.0000456 AC: 49 AN: 1075614

Other (OTH) AF: 0.000349 AC: 20 AN: 57238

GnomAD4 genome AF: 0.00131 AC: 200 AN: 152382 Hom.: 0 Cov.: 34 AF XY: 0.00133 AC XY: 99 AN XY: 74514

African (AFR) AF: 0.00462 AC: 192 AN: 41590

American (AMR) AF: 0.000327 AC: 5 AN: 15310

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

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: 0.0000147 AC: 1 AN: 68038

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000643 Hom.: 0

Bravo AF: 0.00149

ExAC AF: 0.000428 AC: 51

Asia WGS AF: 0.000577 AC: 3 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Dec 24, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	1.1
DANN	Benign	0.95
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.051	N
LIST_S2	Benign	0.61	T
MetaRNN	Benign	0.0030	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.73
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.92	N
REVEL	Benign	0.023
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.091	T
Vest4		0.058
MVP		0.16
MPC		1.0
ClinPred		0.022	T
GERP RS		1.5
Varity_R		0.048
gMVP		0.49
Mutation Taster		=97/3	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: rs72957093; hg19: chr3-126707450;