3-66380387-T-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.3158A>C(p.Gln1053Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.186 in 1,614,060 control chromosomes in the GnomAD database, including 29,674 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.16 (2216 hom., cov: 32)
  • Exomes 𝑓: 0.19 (27458 hom.)
• Consequence: LRIG1 NM_015541.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.40

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]

SLC25A26 (HGNC:20661): (solute carrier family 25 member 26) This gene is a member of the mitochondrial carrier family which includes nuclear-encoded transporters localized on the inner mitochondrial membranes. Members of the family transport important small molecules across the mitochondrial inner membrane. This protein is involved in the transport of S-adenosylmethionine (SAM) into the mitochondria. Mutations in this gene are associated with combined oxidative phosphorylation deficiency 28. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Apr 2017]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.765923E-4).
• BP6: Variant 3-66380387-T-G is Benign according to our data. Variant chr3-66380387-T-G is described in ClinVar as [Benign]. Clinvar id is 403053.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.204 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRIG1	NM_015541.3	c.3158A>C	p.Gln1053Pro	missense_variant	19/19	ENST00000273261.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRIG1	ENST00000273261.8	c.3158A>C	p.Gln1053Pro	missense_variant	19/19	1	NM_015541.3	P1

Frequencies

GnomAD3 genomes AF: 0.159 AC: 24171 AN: 152088 Hom.: 2217 Cov.: 32

Gnomad AFR AF: 0.0950

Gnomad AMI AF: 0.183

Gnomad AMR AF: 0.120

Gnomad ASJ AF: 0.119

Gnomad EAS AF: 0.0617

Gnomad SAS AF: 0.128

Gnomad FIN AF: 0.227

Gnomad MID AF: 0.168

Gnomad NFE AF: 0.207

Gnomad OTH AF: 0.152

GnomAD3 exomes AF: 0.160 AC: 40208 AN: 251116 Hom.: 3651 AF XY: 0.162 AC XY: 22047 AN XY: 135712

Gnomad AFR exome AF: 0.0870

Gnomad AMR exome AF: 0.0910

Gnomad ASJ exome AF: 0.120

Gnomad EAS exome AF: 0.0656

Gnomad SAS exome AF: 0.125

Gnomad FIN exome AF: 0.232

Gnomad NFE exome AF: 0.206

Gnomad OTH exome AF: 0.165

GnomAD4 exome AF: 0.189 AC: 275573 AN: 1461854 Hom.: 27458 Cov.: 33 AF XY: 0.187 AC XY: 135884 AN XY: 727240

Gnomad4 AFR exome AF: 0.0926

Gnomad4 AMR exome AF: 0.0968

Gnomad4 ASJ exome AF: 0.123

Gnomad4 EAS exome AF: 0.0541

Gnomad4 SAS exome AF: 0.125

Gnomad4 FIN exome AF: 0.230

Gnomad4 NFE exome AF: 0.206

Gnomad4 OTH exome AF: 0.167

GnomAD4 genome AF: 0.159 AC: 24168 AN: 152206 Hom.: 2216 Cov.: 32 AF XY: 0.157 AC XY: 11658 AN XY: 74402

Gnomad4 AFR AF: 0.0949

Gnomad4 AMR AF: 0.120

Gnomad4 ASJ AF: 0.119

Gnomad4 EAS AF: 0.0615

Gnomad4 SAS AF: 0.128

Gnomad4 FIN AF: 0.227

Gnomad4 NFE AF: 0.207

Gnomad4 OTH AF: 0.150

Alfa AF: 0.183 Hom.: 5205

Bravo AF: 0.146

TwinsUK AF: 0.206 AC: 765

ALSPAC AF: 0.210 AC: 809

ESP6500AA AF: 0.0967 AC: 426

ESP6500EA AF: 0.201 AC: 1726

ExAC AF: 0.162 AC: 19671

Asia WGS AF: 0.110 AC: 383 AN: 3478

EpiCase AF: 0.200

EpiControl AF: 0.201

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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). -

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 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.23
Cadd	Benign	21
Dann	Benign	0.97
DEOGEN2	Benign	0.12	T;.
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.86	D
MetaRNN	Benign	0.00098	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	M;.
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.43	N;N
REVEL	Benign	0.21
Sift	Uncertain	0.010	D;D
Sift4G	Benign	0.15	T;T
Polyphen		0.23	B;P
Vest4		0.50
MPC		0.14
ClinPred		0.022	T
GERP RS		3.1
Varity_R		0.16
gMVP		0.37

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: rs2279290; hg19: chr3-66430811; COSMIC: COSV56250492; COSMIC: COSV56250492;