chr3-66383252-A-T

Position:

• chr3-66383252-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 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

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 Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRIG1	NM_015541.3	c.2221T>A	p.Leu741Met	missense_variant	15/19	ENST00000273261.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRIG1	ENST00000273261.8	c.2221T>A	p.Leu741Met	missense_variant	15/19	1	NM_015541.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 82

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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;T
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Benign	0.65	N;.
MutationTaster	Benign	0.31	P;P;P
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.33	N;N
REVEL	Uncertain	0.39
Sift	Uncertain	0.0030	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		0.75	P;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

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;