3-66383252-A-G

Variant names:

• chr3-66383252-A-G
• rs900171
• NM_015541.3:c.2221T>C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015541.3(LRIG1):​c.2221T>C​(p.Leu741Leu) variant causes a synonymous change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.592 in 1,613,978 control chromosomes in the GnomAD database, including 285,043 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.63 (30398 hom., cov: 33)
  • Exomes 𝑓: 0.59 (254645 hom.)
• Consequence: LRIG1 NM_015541.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 7.52

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 3-66383252-A-G is Benign according to our data. Variant chr3-66383252-A-G is described in ClinVar as [Benign]. Clinvar id is 403054.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.787 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRIG1	NM_015541.3	c.2221T>C	p.Leu741Leu	synonymous_variant	Exon 15 of 19	ENST00000273261.8	NP_056356.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRIG1	ENST00000273261.8	c.2221T>C	p.Leu741Leu	synonymous_variant	Exon 15 of 19	1	NM_015541.3	ENSP00000273261.3

Frequencies

GnomAD3 genomes AF: 0.628 AC: 95433 AN: 152018 Hom.: 30342 Cov.: 33

Gnomad AFR AF: 0.715

Gnomad AMI AF: 0.418

Gnomad AMR AF: 0.645

Gnomad ASJ AF: 0.474

Gnomad EAS AF: 0.809

Gnomad SAS AF: 0.659

Gnomad FIN AF: 0.580

Gnomad MID AF: 0.564

Gnomad NFE AF: 0.574

Gnomad OTH AF: 0.604

GnomAD3 exomes AF: 0.620 AC: 155916 AN: 251310 Hom.: 49180 AF XY: 0.616 AC XY: 83712 AN XY: 135844

Gnomad AFR exome AF: 0.715

Gnomad AMR exome AF: 0.673

Gnomad ASJ exome AF: 0.475

Gnomad EAS exome AF: 0.823

Gnomad SAS exome AF: 0.650

Gnomad FIN exome AF: 0.584

Gnomad NFE exome AF: 0.571

Gnomad OTH exome AF: 0.593

GnomAD4 exome AF: 0.588 AC: 859452 AN: 1461842 Hom.: 254645 Cov.: 82 AF XY: 0.589 AC XY: 428158 AN XY: 727220

Gnomad4 AFR exome AF: 0.713

Gnomad4 AMR exome AF: 0.668

Gnomad4 ASJ exome AF: 0.476

Gnomad4 EAS exome AF: 0.792

Gnomad4 SAS exome AF: 0.648

Gnomad4 FIN exome AF: 0.589

Gnomad4 NFE exome AF: 0.572

Gnomad4 OTH exome AF: 0.594

GnomAD4 genome AF: 0.628 AC: 95552 AN: 152136 Hom.: 30398 Cov.: 33 AF XY: 0.630 AC XY: 46854 AN XY: 74390

Gnomad4 AFR AF: 0.716

Gnomad4 AMR AF: 0.646

Gnomad4 ASJ AF: 0.474

Gnomad4 EAS AF: 0.808

Gnomad4 SAS AF: 0.660

Gnomad4 FIN AF: 0.580

Gnomad4 NFE AF: 0.574

Gnomad4 OTH AF: 0.607

Alfa AF: 0.581 Hom.: 49027

Bravo AF: 0.635

Asia WGS AF: 0.714 AC: 2482 AN: 3478

EpiCase AF: 0.573

EpiControl AF: 0.571

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

LRIG1-related disorder Benign:1

Oct 17, 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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	9.3
DANN	Benign	0.81

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: rs900171; hg19: chr3-66433676; COSMIC: COSV56239221; COSMIC: COSV56239221;