rs2306272

Variant names:

• chr3-66384219-T-C
• rs2306272
• NM_015541.3:c.1843A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015541.3(LRIG1):​c.1843A>G​(p.Met615Val) variant causes a missense change. The variant allele was found at a frequency of 0.294 in 1,613,766 control chromosomes in the GnomAD database, including 76,066 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (6217 hom., cov: 32)
  • Exomes 𝑓: 0.30 (69849 hom.)
• Consequence: LRIG1 NM_015541.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 6.21
• Publications: 60 publications found

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]

SLC25A26 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• combined oxidative phosphorylation deficiency 28

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=4.7625545E-6).
• BP6: Variant 3-66384219-T-C is Benign according to our data. Variant chr3-66384219-T-C is described in ClinVar as Benign. ClinVar VariationId is 403055.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.709 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015541.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRIG1	NM_015541.3	MANE Select	c.1843A>G	p.Met615Val	missense	Exon 14 of 19	NP_056356.2	Q96JA1-1
	LRIG1	NM_001377344.1		c.1768A>G	p.Met590Val	missense	Exon 13 of 18	NP_001364273.1
	LRIG1	NM_001377345.1		c.1063A>G	p.Met355Val	missense	Exon 14 of 19	NP_001364274.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRIG1	ENST00000273261.8	TSL:1 MANE Select	c.1843A>G	p.Met615Val	missense	Exon 14 of 19	ENSP00000273261.3	Q96JA1-1
	LRIG1	ENST00000383703.3	TSL:1	c.1915A>G	p.Met639Val	missense	Exon 15 of 20	ENSP00000373208.3	Q96JA1-2
	SLC25A26	ENST00000464350.6	TSL:1	n.*1548-1965T>C		intron	N/A	ENSP00000432574.2	H0YCZ5

Frequencies

GnomAD3 genomes AF: 0.262 AC: 39764 AN: 151900 Hom.: 6205 Cov.: 32

Gnomad AFR AF: 0.148

Gnomad AMI AF: 0.180

Gnomad AMR AF: 0.290

Gnomad ASJ AF: 0.251

Gnomad EAS AF: 0.729

Gnomad SAS AF: 0.387

Gnomad FIN AF: 0.250

Gnomad MID AF: 0.291

Gnomad NFE AF: 0.283

Gnomad OTH AF: 0.279

GnomAD2 exomes AF: 0.312 AC: 78294 AN: 250908 AF XY: 0.317

Gnomad AFR exome AF: 0.142

Gnomad AMR exome AF: 0.263

Gnomad ASJ exome AF: 0.250

Gnomad EAS exome AF: 0.746

Gnomad FIN exome AF: 0.250

Gnomad NFE exome AF: 0.282

Gnomad OTH exome AF: 0.304

GnomAD4 exome AF: 0.298 AC: 434876 AN: 1461748 Hom.: 69849 Cov.: 49 AF XY: 0.300 AC XY: 218406 AN XY: 727152

African (AFR) AF: 0.140 AC: 4682 AN: 33478

American (AMR) AF: 0.258 AC: 11554 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.253 AC: 6610 AN: 26136

East Asian (EAS) AF: 0.714 AC: 28342 AN: 39700

South Asian (SAS) AF: 0.371 AC: 31993 AN: 86256

European-Finnish (FIN) AF: 0.258 AC: 13796 AN: 53416

Middle Eastern (MID) AF: 0.274 AC: 1581 AN: 5766

European-Non Finnish (NFE) AF: 0.285 AC: 317277 AN: 1111880

Other (OTH) AF: 0.315 AC: 19041 AN: 60392

GnomAD4 genome AF: 0.262 AC: 39789 AN: 152018 Hom.: 6217 Cov.: 32 AF XY: 0.265 AC XY: 19707 AN XY: 74300

African (AFR) AF: 0.148 AC: 6133 AN: 41502

American (AMR) AF: 0.290 AC: 4423 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.251 AC: 872 AN: 3468

East Asian (EAS) AF: 0.728 AC: 3741 AN: 5136

South Asian (SAS) AF: 0.389 AC: 1871 AN: 4804

European-Finnish (FIN) AF: 0.250 AC: 2645 AN: 10580

Middle Eastern (MID) AF: 0.296 AC: 87 AN: 294

European-Non Finnish (NFE) AF: 0.283 AC: 19253 AN: 67966

Other (OTH) AF: 0.285 AC: 600 AN: 2102

Alfa AF: 0.283 Hom.: 26613

Bravo AF: 0.260

TwinsUK AF: 0.283 AC: 1050

ALSPAC AF: 0.286 AC: 1102

ESP6500AA AF: 0.145 AC: 637

ESP6500EA AF: 0.274 AC: 2358

ExAC AF: 0.313 AC: 38028

Asia WGS AF: 0.502 AC: 1743 AN: 3478

EpiCase AF: 0.288

EpiControl AF: 0.285

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	LRIG1-related disorder (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	19
DANN	Benign	0.72
DEOGEN2	Benign	0.057	T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.10
FATHMM_MKL	Uncertain	0.96	D
MetaRNN	Benign	0.0000048	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.33	N
PhyloP100		6.2
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.33	N
REVEL	Benign	0.069
Sift	Benign	0.37	T
Sift4G	Benign	0.24	T
Polyphen		0.0070	B
Vest4		0.092
MPC		0.13
ClinPred		0.014	T
GERP RS		5.0
Varity_R		0.26
gMVP		0.36
Mutation Taster		=91/9	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2306272; hg19: chr3-66434643; COSMIC: COSV56236993;