chr3-66380453-G-C

Position:

• chr3-66380453-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 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 (no stars). 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 no assertion criteria provided 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 -13 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 no_assertion_criteria_provided, 0 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: no assertion criteria provided

Submissions by phenotype

LRIG1-related disorder Benign:1

Benign, no assertion criteria provided

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;