3-66380635-G-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_015541.3(LRIG1):c.2997C>G(p.Asn999Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000413 in 1,614,226 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00047 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00041 (5 hom.)
• Consequence: LRIG1 NM_015541.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.91

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009337217).
• BP6: Variant 3-66380635-G-C is Benign according to our data. Variant chr3-66380635-G-C is described in ClinVar as [Benign]. Clinvar id is 3045833.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 70 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRIG1	NM_015541.3	c.2997C>G	p.Asn999Lys	missense_variant	18/19	ENST00000273261.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRIG1	ENST00000273261.8	c.2997C>G	p.Asn999Lys	missense_variant	18/19	1	NM_015541.3	P1

Frequencies

GnomAD3 genomes AF: 0.000460 AC: 70 AN: 152226 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00340

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00147 AC: 369 AN: 250984 Hom.: 4 AF XY: 0.00120 AC XY: 163 AN XY: 135724

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.00974

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000194

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.000407 AC: 595 AN: 1461882 Hom.: 5 Cov.: 33 AF XY: 0.000371 AC XY: 270 AN XY: 727242

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.00912

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000140

Gnomad4 OTH exome AF: 0.000364

GnomAD4 genome AF: 0.000473 AC: 72 AN: 152344 Hom.: 1 Cov.: 33 AF XY: 0.000470 AC XY: 35 AN XY: 74492

Gnomad4 AFR AF: 0.000192

Gnomad4 AMR AF: 0.00353

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000236 Hom.: 0

Bravo AF: 0.000816

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00120 AC: 146

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000356

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 11, 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	Uncertain	0.37
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.17
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.36	T;.
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.94	D
MetaRNN	Benign	0.0093	T;T
MetaSVM	Uncertain	0.13	D
MutationAssessor	Uncertain	2.2	M;.
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.2	D;D
REVEL	Uncertain	0.41
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.0080	D;D
Polyphen		1.0	D;D
Vest4		0.84
MutPred		0.27		Gain of ubiquitination at N999 (P = 0.0128);.;
MVP		0.67
MPC		0.17
ClinPred		0.054	T
GERP RS		3.8
Varity_R		0.39
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs140051529; hg19: chr3-66431059; COSMIC: COSV104382678; COSMIC: COSV104382678;