3-66500338-G-C

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• 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
• Publications: 20 publications found

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

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015541.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRIG1	NM_015541.3	MANE Select	c.70C>G	p.Leu24Val	missense	Exon 1 of 19	NP_056356.2
	LRIG1	NM_001377344.1		c.70C>G	p.Leu24Val	missense	Exon 1 of 18	NP_001364273.1
	LRIG1	NM_001377345.1		c.-563+755C>G		intron	N/A	NP_001364274.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRIG1	ENST00000273261.8	TSL:1 MANE Select	c.70C>G	p.Leu24Val	missense	Exon 1 of 19	ENSP00000273261.3
	LRIG1	ENST00000383703.3	TSL:1	c.70C>G	p.Leu24Val	missense	Exon 1 of 20	ENSP00000373208.3
	LRIG1	ENST00000498287.5	TSL:4	n.171+755C>G		intron	N/A

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

GnomAD2 exomes AF: 0.920 AC: 107645 AN: 117024 AF XY: 0.930

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 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

African (AFR) AF: 0.268 AC: 7543 AN: 28156

American (AMR) AF: 0.877 AC: 23934 AN: 27278

Ashkenazi Jewish (ASJ) AF: 0.915 AC: 20832 AN: 22760

East Asian (EAS) AF: 0.832 AC: 26606 AN: 31980

South Asian (SAS) AF: 0.961 AC: 71325 AN: 74224

European-Finnish (FIN) AF: 0.944 AC: 35473 AN: 37578

Middle Eastern (MID) AF: 0.928 AC: 4491 AN: 4838

European-Non Finnish (NFE) AF: 0.989 AC: 1050662 AN: 1062194

Other (OTH) AF: 0.912 AC: 50637 AN: 55528

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

African (AFR) AF: 0.294 AC: 12149 AN: 41350

American (AMR) AF: 0.863 AC: 13130 AN: 15222

Ashkenazi Jewish (ASJ) AF: 0.908 AC: 3144 AN: 3464

East Asian (EAS) AF: 0.809 AC: 4049 AN: 5002

South Asian (SAS) AF: 0.956 AC: 4614 AN: 4824

European-Finnish (FIN) AF: 0.936 AC: 9824 AN: 10496

Middle Eastern (MID) AF: 0.918 AC: 268 AN: 292

European-Non Finnish (NFE) AF: 0.986 AC: 66772 AN: 67740

Other (OTH) AF: 0.803 AC: 1691 AN: 2106

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

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 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

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

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
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		1.3
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.55	N
REVEL	Benign	0.062
Sift	Benign	0.093	T
Sift4G	Benign	0.23	T
Polyphen		0.28	B
Vest4		0.16
MPC		0.095
ClinPred		0.0070	T
GERP RS		3.1
Varity_R		0.13
gMVP		0.49
Mutation Taster		=96/4	polymorphism (auto)

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