Genetic Variant NM_015613.3:c.1165C>A (chr10-84232634-G-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_015613.3(LRIT1):c.1165C>A(p.Pro389Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0707 in 1,613,418 control chromosomes in the GnomAD database, including 12,293 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.18 ( 5356 hom., cov: 32)

Exomes 𝑓: 0.059 ( 6937 hom. )

Consequence

LRIT1
NM_015613.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.00300

Variant links:

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]

LRIT1 links:

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]

RGR links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=2.2184849E-4).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.482 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRIT1	NM_015613.3 link	c.1165C>A	p.Pro389Thr	missense_variant	Exon 4 of 4	ENST00000372105.4	NP_056428.1	Q9P2V4
LRIT1	XM_011539626.3 link	c.580C>A	p.Pro194Thr	missense_variant	Exon 3 of 3		XP_011537928.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRIT1	ENST00000372105.4 link	c.1165C>A	p.Pro389Thr	missense_variant	Exon 4 of 4	1	NM_015613.3	ENSP00000361177.3		Q9P2V4
RGR	ENST00000652073.1 link	c.-459+159G>T		intron_variant	Intron 2 of 7			ENSP00000498800.1		A0A494C063

Frequencies

GnomAD3 genomes

AF:

0.179

AC:

27240

AN:

152028

Hom.:

5344

Cov.:

show subpopulations

Gnomad AFR

AF:

0.488

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.145

Gnomad ASJ

AF:

0.0628

Gnomad EAS

AF:

0.0431

Gnomad SAS

AF:

0.0926

Gnomad FIN

AF:

0.0831

Gnomad MID

AF:

0.0764

Gnomad NFE

AF:

0.0406

Gnomad OTH

AF:

0.141

GnomAD3 exomes

AF:

0.101

AC:

25362

AN:

250728

Hom.:

2989

AF XY:

0.0886

AC XY:

12017

AN XY:

135580

show subpopulations

Gnomad AFR exome

AF:

0.494

Gnomad AMR exome

AF:

0.189

Gnomad ASJ exome

AF:

0.0627

Gnomad EAS exome

AF:

0.0390

Gnomad SAS exome

AF:

0.0862

Gnomad FIN exome

AF:

0.0834

Gnomad NFE exome

AF:

0.0405

Gnomad OTH exome

AF:

0.0797

GnomAD4 exome

AF:

0.0593

AC:

86725

AN:

1461272

Hom.:

6937

Cov.:

AF XY:

0.0582

AC XY:

42321

AN XY:

726816

show subpopulations

Gnomad4 AFR exome

AF:

0.509

Gnomad4 AMR exome

AF:

0.183

Gnomad4 ASJ exome

AF:

0.0605

Gnomad4 EAS exome

AF:

0.0348

Gnomad4 SAS exome

AF:

0.0846

Gnomad4 FIN exome

AF:

0.0818

Gnomad4 NFE exome

AF:

0.0375

Gnomad4 OTH exome

AF:

0.0802

GnomAD4 genome

AF:

0.179

AC:

27277

AN:

152146

Hom.:

5356

Cov.:

AF XY:

0.178

AC XY:

13215

AN XY:

74396

show subpopulations

Gnomad4 AFR

AF:

0.488

Gnomad4 AMR

AF:

0.145

Gnomad4 ASJ

AF:

0.0628

Gnomad4 EAS

AF:

0.0432

Gnomad4 SAS

AF:

0.0919

Gnomad4 FIN

AF:

0.0831

Gnomad4 NFE

AF:

0.0406

Gnomad4 OTH

AF:

0.139

Alfa

AF:

0.0761

Hom.:

2010

Bravo

AF:

0.200

TwinsUK

AF:

0.0383

AC:

142

ALSPAC

AF:

0.0355

AC:

137

ESP6500AA

AF:

0.470

AC:

2073

ESP6500EA

AF:

0.0443

AC:

381

ExAC

AF:

0.104

AC:

12664

Asia WGS

AF:

0.0870

AC:

307

AN:

3478

EpiCase

AF:

0.0398

EpiControl

AF:

0.0390

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.75

BayesDel_noAF

Benign

-0.71

CADD

Benign

4.6

DANN

Benign

0.33

DEOGEN2

Benign

0.010

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.041

LIST_S2

Benign

0.53

MetaRNN

Benign

0.00022

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.0

PrimateAI

Benign

0.24

PROVEAN

Benign

-1.1

REVEL

Benign

0.045

Sift

Benign

0.47

Sift4G

Benign

0.12

Polyphen

0.036

Vest4

0.015

MPC

0.090

ClinPred

0.0029

GERP RS

2.8

Varity_R

0.048

gMVP

0.45

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over