rs1403625

Positions:

• chr3-66500332-G-C
• chr3-66500332-G-T

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.76C>G​(p.Leu26Val) 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 1,494,546 control chromosomes in the GnomAD database, including 679,457 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.77 (51660 hom., cov: 31)
  • Exomes 𝑓: 0.96 (627797 hom.)
• Consequence: LRIG1 NM_015541.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.33

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=8.704122E-7).
• BP6: Variant 3-66500332-G-C is Benign according to our data. Variant chr3-66500332-G-C is described in ClinVar as [Benign]. Clinvar id is 403057.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/exons	MANE	UniProt
LRIG1	NM_015541.3	c.76C>G	p.Leu26Val	missense_variant	1/19	ENST00000273261.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRIG1	ENST00000273261.8	c.76C>G	p.Leu26Val	missense_variant	1/19	1	NM_015541.3	P1
LRIG1	ENST00000383703.3	c.76C>G	p.Leu26Val	missense_variant	1/20	1
LRIG1	ENST00000498287.5	n.171+761C>G		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.770 AC: 116518 AN: 151252 Hom.: 51655 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: 0.804

GnomAD3 exomes AF: 0.920 AC: 105493 AN: 114698 Hom.: 49641 AF XY: 0.930 AC XY: 60735 AN XY: 65290

Gnomad AFR exome AF: 0.248

Gnomad AMR exome AF: 0.877

Gnomad ASJ exome AF: 0.910

Gnomad EAS exome AF: 0.807

Gnomad SAS exome AF: 0.962

Gnomad FIN exome AF: 0.929

Gnomad NFE exome AF: 0.985

Gnomad OTH exome AF: 0.921

GnomAD4 exome AF: 0.961 AC: 1290177 AN: 1343186 Hom.: 627797 Cov.: 50 AF XY: 0.963 AC XY: 639956 AN XY: 664780

Gnomad4 AFR exome AF: 0.268

Gnomad4 AMR exome AF: 0.878

Gnomad4 ASJ exome AF: 0.915

Gnomad4 EAS exome AF: 0.832

Gnomad4 SAS exome AF: 0.961

Gnomad4 FIN exome AF: 0.943

Gnomad4 NFE exome AF: 0.989

Gnomad4 OTH exome AF: 0.912

GnomAD4 genome AF: 0.770 AC: 116535 AN: 151360 Hom.: 51660 Cov.: 31 AF XY: 0.772 AC XY: 57085 AN XY: 73970

Gnomad4 AFR AF: 0.294

Gnomad4 AMR AF: 0.863

Gnomad4 ASJ AF: 0.908

Gnomad4 EAS AF: 0.809

Gnomad4 SAS AF: 0.957

Gnomad4 FIN AF: 0.936

Gnomad4 NFE AF: 0.986

Gnomad4 OTH AF: 0.803

Alfa AF: 0.796 Hom.: 3308

Bravo AF: 0.741

ESP6500AA AF: 0.484 AC: 1298

ESP6500EA AF: 0.983 AC: 5191

ExAC AF: 0.883 AC: 85766

Asia WGS AF: 0.820 AC: 2812 AN: 3430

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

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

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 21, 2019

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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	15
DANN	Benign	0.83
DEOGEN2	Benign	0.094	T;.
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.60	D
MetaRNN	Benign	8.7e-7	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.8	L;L
MutationTaster	Benign	1.0	P;P
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.58	N;N
REVEL	Benign	0.068
Sift	Benign	0.35	T;T
Sift4G	Benign	0.25	T;T
Polyphen		0.48	P;P
Vest4		0.19
MPC		0.16
ClinPred		0.0070	T
GERP RS		2.9
Varity_R		0.057
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1403625; hg19: chr3-66550756; COSMIC: COSV56236825; COSMIC: COSV56236825;