7-111122864-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001099658.2(LRRN3):c.92G>A(p.Arg31Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00254 in 1,613,876 control chromosomes in the GnomAD database, including 129 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R31W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0043 (23 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (106 hom.)
• Consequence: LRRN3 NM_001099658.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.87

Genes affected

LRRN3 (HGNC:17200): (leucine rich repeat neuronal 3) Predicted to act upstream of or within positive regulation of synapse assembly. Predicted to be integral component of membrane. Predicted to be active in extracellular matrix and extracellular space. [provided by Alliance of Genome Resources, Apr 2022]

IMMP2L (HGNC:14598): (inner mitochondrial membrane peptidase subunit 2) This gene encodes a protein involved in processing the signal peptide sequences used to direct mitochondrial proteins to the mitochondria. The encoded protein resides in the mitochondria and is one of the necessary proteins for the catalytic activity of the mitochondrial inner membrane peptidase (IMP) complex. Two variants that encode the same protein have been described for this gene. [provided by RefSeq, Sep 2011]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0031238496).
• BP6: Variant 7-111122864-G-A is Benign according to our data. Variant chr7-111122864-G-A is described in ClinVar as [Benign]. Clinvar id is 778353.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.059 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRRN3	NM_001099658.2	c.92G>A	p.Arg31Gln	missense_variant	3/3	ENST00000308478.10
IMMP2L	NM_032549.4	c.240-159299C>T		intron_variant		ENST00000405709.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRRN3	ENST00000308478.10	c.92G>A	p.Arg31Gln	missense_variant	3/3	1	NM_001099658.2	P1
IMMP2L	ENST00000405709.7	c.240-159299C>T		intron_variant		1	NM_032549.4	P1

Frequencies

GnomAD3 genomes AF: 0.00428 AC: 651 AN: 152092 Hom.: 23 Cov.: 32

Gnomad AFR AF: 0.000604

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0376

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00616

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00945 AC: 2372 AN: 251048 Hom.: 87 AF XY: 0.00700 AC XY: 950 AN XY: 135668

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.0640

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00550

Gnomad SAS exome AF: 0.000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00539

GnomAD4 exome AF: 0.00235 AC: 3442 AN: 1461666 Hom.: 106 Cov.: 33 AF XY: 0.00200 AC XY: 1457 AN XY: 727148

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.0609

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0114

Gnomad4 SAS exome AF: 0.000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000639

Gnomad4 OTH exome AF: 0.00217

GnomAD4 genome AF: 0.00428 AC: 652 AN: 152210 Hom.: 23 Cov.: 32 AF XY: 0.00511 AC XY: 380 AN XY: 74400

Gnomad4 AFR AF: 0.000602

Gnomad4 AMR AF: 0.0376

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00618

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.000600 Hom.: 1

Bravo AF: 0.00671

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00749 AC: 909

Asia WGS AF: 0.00577 AC: 20 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 07, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.20
Cadd	Benign	13
Dann	Benign	0.84
DEOGEN2	Benign	0.0023	T;T;T;.
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.33	N
MetaRNN	Benign	0.0031	T;T;T;T
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	-1.0	N;N;N;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;N;N;N
PrimateAI	Benign	0.21	T
PROVEAN	Benign	0.33	N;N;N;N
REVEL	Uncertain	0.33
Sift	Benign	0.67	T;T;T;T
Sift4G	Benign	0.62	T;T;T;T
Polyphen		0.0	B;B;B;.
Vest4		0.096
MVP		0.54
MPC		0.26
ClinPred		0.0023	T
GERP RS		0.94
Varity_R		0.034
gMVP		0.10

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

Publications

LitVar

Other links and lift over

dbSNP: rs186329804; hg19: chr7-110762920;