chr3-66380680-G-A

Position:

• chr3-66380680-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_015541.3(LRIG1):​c.2952C>T​(p.Ala984=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00223 in 1,614,162 control chromosomes in the GnomAD database, including 78 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (44 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (34 hom.)
• Consequence: LRIG1 NM_015541.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.251

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 3-66380680-G-A is Benign according to our data. Variant chr3-66380680-G-A is described in ClinVar as [Benign]. Clinvar id is 791935.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.251 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0112 (1704/152302) while in subpopulation AFR AF= 0.0385 (1600/41552). AF 95% confidence interval is 0.0369. There are 44 homozygotes in gnomad4. There are 787 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1704 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRIG1	NM_015541.3	c.2952C>T	p.Ala984=	synonymous_variant	18/19	ENST00000273261.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRIG1	ENST00000273261.8	c.2952C>T	p.Ala984=	synonymous_variant	18/19	1	NM_015541.3	P1

Frequencies

GnomAD3 genomes AF: 0.0112 AC: 1697 AN: 152184 Hom.: 45 Cov.: 33

Gnomad AFR AF: 0.0385

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00353

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.00909

GnomAD3 exomes AF: 0.00296 AC: 743 AN: 251322 Hom.: 11 AF XY: 0.00213 AC XY: 289 AN XY: 135870

Gnomad AFR exome AF: 0.0393

Gnomad AMR exome AF: 0.00168

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.000381

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000229

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.00130 AC: 1902 AN: 1461860 Hom.: 34 Cov.: 33 AF XY: 0.00120 AC XY: 874 AN XY: 727226

Gnomad4 AFR exome AF: 0.0420

Gnomad4 AMR exome AF: 0.00215

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.000176

Gnomad4 SAS exome AF: 0.000278

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.000147

Gnomad4 OTH exome AF: 0.00285

GnomAD4 genome AF: 0.0112 AC: 1704 AN: 152302 Hom.: 44 Cov.: 33 AF XY: 0.0106 AC XY: 787 AN XY: 74478

Gnomad4 AFR AF: 0.0385

Gnomad4 AMR AF: 0.00353

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000338

Gnomad4 OTH AF: 0.00900

Alfa AF: 0.00528 Hom.: 7

Bravo AF: 0.0126

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.000415

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 15, 2018	- -

LRIG1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 23, 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
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.73
DANN	Benign	0.62
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs35938214; hg19: chr3-66431104;