chr3-66383252-A-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_015541.3(LRIG1):​c.2221T>A​(p.Leu741Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L741L) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: LRIG1 NM_015541.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.52
• Publications: 23 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.2221T>A	p.Leu741Met	missense	Exon 15 of 19	NP_056356.2	Q96JA1-1
	LRIG1	NM_001377344.1		c.2146T>A	p.Leu716Met	missense	Exon 14 of 18	NP_001364273.1
	LRIG1	NM_001377345.1		c.1441T>A	p.Leu481Met	missense	Exon 15 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.2221T>A	p.Leu741Met	missense	Exon 15 of 19	ENSP00000273261.3	Q96JA1-1
	LRIG1	ENST00000383703.3	TSL:1	c.2152T>A	p.Leu718Met	missense	Exon 16 of 20	ENSP00000373208.3	Q96JA1-2
	SLC25A26	ENST00000464350.6	TSL:1	n.*1547+2299A>T		intron	N/A	ENSP00000432574.2	H0YCZ5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 82

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.055	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.088	T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Benign	0.040	D
MetaRNN	Uncertain	0.48	T
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Benign	0.65	N
PhyloP100		7.5
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.33	N
REVEL	Uncertain	0.39
Sift	Uncertain	0.0030	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.75	P
Vest4		0.35
MutPred		0.75		Gain of glycosylation at T736 (P = 0.0383)
MVP		0.093
MPC		0.30
ClinPred		0.72	D
GERP RS		5.7
Varity_R		0.66
gMVP		0.39
Mutation Taster		=64/36	polymorphism

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: rs900171; hg19: chr3-66433676;