3-66380763-C-T

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.2869G>A(p.Ala957Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0462 in 1,614,116 control chromosomes in the GnomAD database, including 2,594 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 0.080 (682 hom., cov: 33)
  • Exomes 𝑓: 0.043 (1912 hom.)
• Consequence: LRIG1 NM_015541.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.37

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=9.95487E-4).
• BP6: Variant 3-66380763-C-T is Benign according to our data. Variant chr3-66380763-C-T is described in ClinVar as [Benign]. Clinvar id is 3055912.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.156 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRIG1	NM_015541.3	c.2869G>A	p.Ala957Thr	missense_variant	18/19	ENST00000273261.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRIG1	ENST00000273261.8	c.2869G>A	p.Ala957Thr	missense_variant	18/19	1	NM_015541.3	P1

Frequencies

GnomAD3 genomes AF: 0.0795 AC: 12093 AN: 152130 Hom.: 683 Cov.: 33

Gnomad AFR AF: 0.159

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.0707

Gnomad ASJ AF: 0.0389

Gnomad EAS AF: 0.0129

Gnomad SAS AF: 0.0201

Gnomad FIN AF: 0.0933

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0434

Gnomad OTH AF: 0.0774

GnomAD3 exomes AF: 0.0536 AC: 13479 AN: 251386 Hom.: 569 AF XY: 0.0487 AC XY: 6624 AN XY: 135886

Gnomad AFR exome AF: 0.161

Gnomad AMR exome AF: 0.0726

Gnomad ASJ exome AF: 0.0386

Gnomad EAS exome AF: 0.0115

Gnomad SAS exome AF: 0.0154

Gnomad FIN exome AF: 0.0933

Gnomad NFE exome AF: 0.0432

Gnomad OTH exome AF: 0.0570

GnomAD4 exome AF: 0.0427 AC: 62459 AN: 1461868 Hom.: 1912 Cov.: 33 AF XY: 0.0418 AC XY: 30374 AN XY: 727232

Gnomad4 AFR exome AF: 0.165

Gnomad4 AMR exome AF: 0.0731

Gnomad4 ASJ exome AF: 0.0378

Gnomad4 EAS exome AF: 0.0182

Gnomad4 SAS exome AF: 0.0170

Gnomad4 FIN exome AF: 0.0895

Gnomad4 NFE exome AF: 0.0384

Gnomad4 OTH exome AF: 0.0467

GnomAD4 genome AF: 0.0795 AC: 12104 AN: 152248 Hom.: 682 Cov.: 33 AF XY: 0.0805 AC XY: 5993 AN XY: 74432

Gnomad4 AFR AF: 0.159

Gnomad4 AMR AF: 0.0705

Gnomad4 ASJ AF: 0.0389

Gnomad4 EAS AF: 0.0130

Gnomad4 SAS AF: 0.0199

Gnomad4 FIN AF: 0.0933

Gnomad4 NFE AF: 0.0434

Gnomad4 OTH AF: 0.0780

Alfa AF: 0.0466 Hom.: 554

Bravo AF: 0.0821

TwinsUK AF: 0.0391 AC: 145

ALSPAC AF: 0.0348 AC: 134

ESP6500AA AF: 0.160 AC: 706

ESP6500EA AF: 0.0423 AC: 364

ExAC AF: 0.0548 AC: 6654

Asia WGS AF: 0.0450 AC: 158 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

Nov 06, 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	0.089
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.68
Cadd	Benign	0.0030
Dann	Benign	0.68
DEOGEN2	Benign	0.045	T;.
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.039	N
MetaRNN	Benign	0.0010	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.77	N;.
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.14	N;N
REVEL	Benign	0.13
Sift	Benign	0.70	T;T
Sift4G	Benign	0.47	T;T
Polyphen		0.0	B;B
Vest4		0.017
MPC		0.089
ClinPred		0.0031	T
GERP RS		-12
Varity_R		0.013
gMVP		0.0087

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: rs332373; hg19: chr3-66431187; COSMIC: COSV56250705; COSMIC: COSV56250705;