3-66380453-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_015541.3(LRIG1):c.3092C>G(p.Pro1031Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0459 in 1,614,004 control chromosomes in the GnomAD database, including 2,405 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 (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.075 (570 hom., cov: 33)
  • Exomes 𝑓: 0.043 (1835 hom.)
• Consequence: LRIG1 NM_015541.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0600

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015669763).
• BP6: Variant 3-66380453-G-C is Benign according to our data. Variant chr3-66380453-G-C is described in ClinVar as [Benign]. Clinvar id is 3056821.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.139 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRIG1	NM_015541.3	c.3092C>G	p.Pro1031Arg	missense_variant	19/19	ENST00000273261.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRIG1	ENST00000273261.8	c.3092C>G	p.Pro1031Arg	missense_variant	19/19	1	NM_015541.3	P1

Frequencies

GnomAD3 genomes AF: 0.0749 AC: 11386 AN: 152038 Hom.: 571 Cov.: 33

Gnomad AFR AF: 0.142

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.0683

Gnomad ASJ AF: 0.0389

Gnomad EAS AF: 0.0141

Gnomad SAS AF: 0.0317

Gnomad FIN AF: 0.0934

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0434

Gnomad OTH AF: 0.0718

GnomAD3 exomes AF: 0.0539 AC: 13427 AN: 249332 Hom.: 536 AF XY: 0.0496 AC XY: 6694 AN XY: 134874

Gnomad AFR exome AF: 0.143

Gnomad AMR exome AF: 0.0722

Gnomad ASJ exome AF: 0.0387

Gnomad EAS exome AF: 0.0118

Gnomad SAS exome AF: 0.0256

Gnomad FIN exome AF: 0.0935

Gnomad NFE exome AF: 0.0434

Gnomad OTH exome AF: 0.0574

GnomAD4 exome AF: 0.0429 AC: 62680 AN: 1461848 Hom.: 1835 Cov.: 33 AF XY: 0.0423 AC XY: 30745 AN XY: 727226

Gnomad4 AFR exome AF: 0.147

Gnomad4 AMR exome AF: 0.0724

Gnomad4 ASJ exome AF: 0.0378

Gnomad4 EAS exome AF: 0.0201

Gnomad4 SAS exome AF: 0.0273

Gnomad4 FIN exome AF: 0.0898

Gnomad4 NFE exome AF: 0.0384

Gnomad4 OTH exome AF: 0.0460

GnomAD4 genome AF: 0.0749 AC: 11393 AN: 152156 Hom.: 570 Cov.: 33 AF XY: 0.0765 AC XY: 5689 AN XY: 74404

Gnomad4 AFR AF: 0.142

Gnomad4 AMR AF: 0.0681

Gnomad4 ASJ AF: 0.0389

Gnomad4 EAS AF: 0.0141

Gnomad4 SAS AF: 0.0313

Gnomad4 FIN AF: 0.0934

Gnomad4 NFE AF: 0.0434

Gnomad4 OTH AF: 0.0725

Alfa AF: 0.0381 Hom.: 117

Bravo AF: 0.0764

TwinsUK AF: 0.0378 AC: 140

ALSPAC AF: 0.0337 AC: 130

ESP6500AA AF: 0.143 AC: 628

ESP6500EA AF: 0.0420 AC: 361

ExAC AF: 0.0548 AC: 6648

Asia WGS AF: 0.0530 AC: 186 AN: 3478

EpiCase AF: 0.0357

EpiControl AF: 0.0381

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

LRIG1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 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	0.11
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	13
Dann	Uncertain	0.99
DEOGEN2	Benign	0.12	T;.
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.19	N
MetaRNN	Benign	0.0016	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L;.
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.4	N;N
REVEL	Benign	0.090
Sift	Uncertain	0.025	D;D
Sift4G	Uncertain	0.047	D;D
Polyphen		0.83	P;P
Vest4		0.50
MPC		0.15
ClinPred		0.0040	T
GERP RS		1.6
Varity_R		0.037
gMVP		0.079

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: rs332374; hg19: chr3-66430877;