rs376610215

Positions:

chr4-109869732-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_198506.5(LRIT3):c.983G>A(p.Cys328Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000217 in 1,612,756 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

LRIT3
NM_198506.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:1

Conservation

PhyloP100: 9.38

Variant links:

Genes affected

LRIT3 (HGNC:24783): (leucine rich repeat, Ig-like and transmembrane domains 3) This gene encodes a protein that has a fibronectin type III domain and a C-terminal transmembrane domain, as well as a leucine-rich repeat domain and immunoglobulin-like domain near the N-terminus. The encoded protein may regulate fibroblast growth factor receptors and affect the modification of these receptors, which are glycosylated differently in the Golgi and endoplasmic reticulum. Mutations in this gene are associated with congenital stationary night blindness, type 1F. [provided by RefSeq, May 2013]

LRIT3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.966

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRIT3	NM_198506.5 linkuse as main transcript	c.983G>A	p.Cys328Tyr	missense_variant	4/4	ENST00000594814.6	NP_940908.3
LRIT3	XM_017008167.2 linkuse as main transcript	c.434G>A	p.Cys145Tyr	missense_variant	3/3		XP_016863656.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRIT3	ENST00000594814.6 linkuse as main transcript	c.983G>A	p.Cys328Tyr	missense_variant	4/4	5	NM_198506.5	ENSP00000469759	P1	Q3SXY7-1
LRIT3	ENST00000327908.3 linkuse as main transcript	c.434G>A	p.Cys145Tyr	missense_variant	4/4	2		ENSP00000328222

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

250532

Hom.:

AF XY:

0.00000739

AC XY:

AN XY:

135342

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000441

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000219

AC:

AN:

1460554

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

726394

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000216

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Congenital stationary night blindness 1F

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 10, 2013

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 22, 2022

This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 328 of the LRIT3 protein (p.Cys328Tyr). This variant is present in population databases (rs376610215, gnomAD 0.004%). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 39438). This missense change has been observed in individual(s) with congenital stationary night blindness (PMID: 23246293). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.31

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.33

T;.

Eigen

Pathogenic

0.92

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.90

D;D

M_CAP

Uncertain

0.24

MetaRNN

Pathogenic

0.97

D;D

MetaSVM

Uncertain

0.65

MutationAssessor

Pathogenic

4.8

H;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.71

PROVEAN

Pathogenic

-10

.;D

REVEL

Pathogenic

0.73

Sift

Pathogenic

0.0

.;D

Sift4G

Uncertain

0.0020

D;D

Vest4

0.93

MVP

0.59

MPC

0.33

ClinPred

1.0

GERP RS

4.7

Varity_R

0.97

gMVP

0.96

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over