3-66500338-G-C

Variant names:

• chr3-66500338-G-C
• rs1403626
• NM_015541.3:c.70C>G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015541.3(LRIG1):​c.70C>G​(p.Leu24Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.941 in 1,495,944 control chromosomes in the GnomAD database, including 680,117 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.77 (51667 hom., cov: 31)
  • Exomes 𝑓: 0.96 (628450 hom.)
• Consequence: LRIG1 NM_015541.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.34

Genes affected

LRIG1 (HGNC:17360): (leucine rich repeats and immunoglobulin like domains 1) Predicted to act upstream of or within several processes, including innervation; otolith morphogenesis; and sensory perception of sound. Predicted to be located in plasma membrane. Predicted to be active in extracellular matrix and extracellular space. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.33378E-7).
• BP6: Variant 3-66500338-G-C is Benign according to our data. Variant chr3-66500338-G-C is described in ClinVar as [Benign]. Clinvar id is 403058.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.979 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRIG1	NM_015541.3	c.70C>G	p.Leu24Val	missense_variant	Exon 1 of 19	ENST00000273261.8	NP_056356.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRIG1	ENST00000273261.8	c.70C>G	p.Leu24Val	missense_variant	Exon 1 of 19	1	NM_015541.3	ENSP00000273261.3
LRIG1	ENST00000383703.3	c.70C>G	p.Leu24Val	missense_variant	Exon 1 of 20	1		ENSP00000373208.3
LRIG1	ENST00000498287.5	n.171+755C>G		intron_variant	Intron 1 of 5	4

Frequencies

GnomAD3 genomes AF: 0.770 AC: 116535 AN: 151300 Hom.: 51662 Cov.: 31

Gnomad AFR AF: 0.294

Gnomad AMI AF: 0.999

Gnomad AMR AF: 0.862

Gnomad ASJ AF: 0.908

Gnomad EAS AF: 0.809

Gnomad SAS AF: 0.956

Gnomad FIN AF: 0.936

Gnomad MID AF: 0.920

Gnomad NFE AF: 0.986

Gnomad OTH AF: 0.805

GnomAD3 exomes AF: 0.920 AC: 107645 AN: 117024 Hom.: 50671 AF XY: 0.930 AC XY: 62009 AN XY: 66648

Gnomad AFR exome AF: 0.248

Gnomad AMR exome AF: 0.876

Gnomad ASJ exome AF: 0.911

Gnomad EAS exome AF: 0.806

Gnomad SAS exome AF: 0.962

Gnomad FIN exome AF: 0.930

Gnomad NFE exome AF: 0.985

Gnomad OTH exome AF: 0.922

GnomAD4 exome AF: 0.961 AC: 1291503 AN: 1344536 Hom.: 628450 Cov.: 52 AF XY: 0.963 AC XY: 640759 AN XY: 665604

Gnomad4 AFR exome AF: 0.268

Gnomad4 AMR exome AF: 0.877

Gnomad4 ASJ exome AF: 0.915

Gnomad4 EAS exome AF: 0.832

Gnomad4 SAS exome AF: 0.961

Gnomad4 FIN exome AF: 0.944

Gnomad4 NFE exome AF: 0.989

Gnomad4 OTH exome AF: 0.912

GnomAD4 genome AF: 0.770 AC: 116552 AN: 151408 Hom.: 51667 Cov.: 31 AF XY: 0.772 AC XY: 57076 AN XY: 73978

Gnomad4 AFR AF: 0.294

Gnomad4 AMR AF: 0.863

Gnomad4 ASJ AF: 0.908

Gnomad4 EAS AF: 0.809

Gnomad4 SAS AF: 0.956

Gnomad4 FIN AF: 0.936

Gnomad4 NFE AF: 0.986

Gnomad4 OTH AF: 0.803

Alfa AF: 0.793 Hom.: 3163

Bravo AF: 0.741

ESP6500AA AF: 0.475 AC: 1309

ESP6500EA AF: 0.983 AC: 5325

ExAC AF: 0.882 AC: 85758

Asia WGS AF: 0.820 AC: 2815 AN: 3434

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

LRIG1-related disorder Benign:1

Oct 21, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	16
DANN	Benign	0.90
DEOGEN2	Benign	0.076	T;.
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.50	D
MetaRNN	Benign	7.3e-7	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.0	M;M
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.55	N;N
REVEL	Benign	0.062
Sift	Benign	0.093	T;T
Sift4G	Benign	0.23	T;T
Polyphen		0.28	B;P
Vest4		0.16
MPC		0.095
ClinPred		0.0070	T
GERP RS		3.1
Varity_R		0.13
gMVP		0.49

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: rs1403626; hg19: chr3-66550762; COSMIC: COSV56236839; COSMIC: COSV56236839;