chr10-84232422-G-C

Position:

• chr10-84232422-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015613.3(LRIT1):​c.1377C>G​(p.Phe459Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: LRIT1 NM_015613.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.77

Genes affected

LRIT1 (HGNC:23404): (leucine rich repeat, Ig-like and transmembrane domains 1) Predicted to be integral component of endoplasmic reticulum membrane. [provided by Alliance of Genome Resources, Apr 2022]

RGR (HGNC:9990): (retinal G protein coupled receptor) This gene encodes a putative retinal G-protein coupled receptor. The gene is a member of the opsin subfamily of the 7 transmembrane, G-protein coupled receptor 1 family. Like other opsins which bind retinaldehyde, it contains a conserved lysine residue in the seventh transmembrane domain. The protein acts as a photoisomerase to catalyze the conversion of all-trans-retinal to 11-cis-retinal. The reverse isomerization occurs with rhodopsin in retinal photoreceptor cells. The protein is exclusively expressed in tissue adjacent to retinal photoreceptor cells, the retinal pigment epithelium and Mueller cells. This gene may be associated with autosomal recessive and autosomal dominant retinitis pigmentosa (arRP and adRP, respectively). Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14765769).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRIT1	NM_015613.3	c.1377C>G	p.Phe459Leu	missense_variant	4/4	ENST00000372105.4
LRIT1	XM_011539626.3	c.792C>G	p.Phe264Leu	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRIT1	ENST00000372105.4	c.1377C>G	p.Phe459Leu	missense_variant	4/4	1	NM_015613.3	P1
RGR	ENST00000652073.1	c.-512G>C		5_prime_UTR_variant	2/8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 17, 2023

The c.1377C>G (p.F459L) alteration is located in exon 4 (coding exon 4) of the LRIT1 gene. This alteration results from a C to G substitution at nucleotide position 1377, causing the phenylalanine (F) at amino acid position 459 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	18
DANN	Benign	0.94
DEOGEN2	Benign	0.035	T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.0064	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.93	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.070
Sift	Benign	0.41	T
Sift4G	Benign	0.21	T
Polyphen		0.0050	B
Vest4		0.11
MutPred		0.52		Loss of catalytic residue at F459 (P = 0.0201);
MVP		0.36
MPC		0.14
ClinPred		0.40	T
GERP RS		1.7
Varity_R		0.10
gMVP		0.56

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-85992178;