3-66380387-T-G

Variant names:

• chr3-66380387-T-G
• rs2279290
• NM_015541.3:c.3158A>C

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.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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• 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:3
• Conservation: PhyloP100: 2.40
• Publications: 34 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]

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]

SLC25A26 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• combined oxidative phosphorylation deficiency 28

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

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.3158A>C	p.Gln1053Pro	missense	Exon 19 of 19	NP_056356.2
	LRIG1	NM_001377344.1		c.3083A>C	p.Gln1028Pro	missense	Exon 18 of 18	NP_001364273.1
	LRIG1	NM_001377345.1		c.2378A>C	p.Gln793Pro	missense	Exon 19 of 19	NP_001364274.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRIG1	ENST00000273261.8	TSL:1 MANE Select	c.3158A>C	p.Gln1053Pro	missense	Exon 19 of 19	ENSP00000273261.3
	LRIG1	ENST00000383703.3	TSL:1	c.3089A>C	p.Gln1030Pro	missense	Exon 20 of 20	ENSP00000373208.3
	SLC25A26	ENST00000464350.6	TSL:1	n.*981T>G		non_coding_transcript_exon	Exon 12 of 13	ENSP00000432574.2

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

GnomAD2 exomes AF: 0.160 AC: 40208 AN: 251116 AF XY: 0.162

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 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

African (AFR) AF: 0.0926 AC: 3099 AN: 33480

American (AMR) AF: 0.0968 AC: 4329 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.123 AC: 3207 AN: 26136

East Asian (EAS) AF: 0.0541 AC: 2148 AN: 39696

South Asian (SAS) AF: 0.125 AC: 10780 AN: 86258

European-Finnish (FIN) AF: 0.230 AC: 12276 AN: 53414

Middle Eastern (MID) AF: 0.138 AC: 796 AN: 5768

European-Non Finnish (NFE) AF: 0.206 AC: 228861 AN: 1111984

Other (OTH) AF: 0.167 AC: 10077 AN: 60394

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

African (AFR) AF: 0.0949 AC: 3943 AN: 41538

American (AMR) AF: 0.120 AC: 1841 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.119 AC: 413 AN: 3472

East Asian (EAS) AF: 0.0615 AC: 318 AN: 5172

South Asian (SAS) AF: 0.128 AC: 619 AN: 4822

European-Finnish (FIN) AF: 0.227 AC: 2403 AN: 10582

Middle Eastern (MID) AF: 0.163 AC: 48 AN: 294

European-Non Finnish (NFE) AF: 0.207 AC: 14099 AN: 68000

Other (OTH) AF: 0.150 AC: 317 AN: 2112

Alfa AF: 0.181 Hom.: 10271

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: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	0.093
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
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	M
PhyloP100		2.4
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.43	N
REVEL	Benign	0.21
Sift	Uncertain	0.010	D
Sift4G	Benign	0.15	T
Polyphen		0.23	B
Vest4		0.50
MPC		0.14
ClinPred		0.022	T
GERP RS		3.1
Varity_R		0.16
gMVP		0.37
Mutation Taster		=94/6	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: rs2279290; hg19: chr3-66430811; COSMIC: COSV56250492; COSMIC: COSV56250492;