chr4-109870370-A-G

Variant names:

• chr4-109870370-A-G
• rs35997283
• NM_198506.5:c.1621A>G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_198506.5(LRIT3):​c.1621A>G​(p.Ile541Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00718 in 1,614,226 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0046 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0075 (46 hom.)
• Consequence: LRIT3 NM_198506.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.66
• Publications: 9 publications found

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 Gene-Disease associations (from GenCC):

• congenital stationary night blindness 1F

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• congenital stationary night blindness

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000296171 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0043292046).
• BP6: Variant 4-109870370-A-G is Benign according to our data. Variant chr4-109870370-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 197396.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 7 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198506.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRIT3	NM_198506.5	MANE Select	c.1621A>G	p.Ile541Val	missense	Exon 4 of 4	NP_940908.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRIT3	ENST00000594814.6	TSL:5 MANE Select	c.1621A>G	p.Ile541Val	missense	Exon 4 of 4	ENSP00000469759.1
	LRIT3	ENST00000327908.3	TSL:2	c.1072A>G	p.Ile358Val	missense	Exon 4 of 4	ENSP00000328222.3
	ENSG00000296171	ENST00000737086.1		n.175-11851T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00462 AC: 703 AN: 152230 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00150

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00281

Gnomad ASJ AF: 0.00720

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.00254

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00766

Gnomad OTH AF: 0.00621

GnomAD2 exomes AF: 0.00509 AC: 1279 AN: 251140 AF XY: 0.00540

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.00231

Gnomad ASJ exome AF: 0.00874

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00291

Gnomad NFE exome AF: 0.00806

Gnomad OTH exome AF: 0.00620

GnomAD4 exome AF: 0.00745 AC: 10891 AN: 1461878 Hom.: 46 Cov.: 36 AF XY: 0.00743 AC XY: 5404 AN XY: 727242

African (AFR) AF: 0.000717 AC: 24 AN: 33480

American (AMR) AF: 0.00268 AC: 120 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00968 AC: 253 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.00246 AC: 212 AN: 86250

European-Finnish (FIN) AF: 0.00417 AC: 223 AN: 53420

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5768

European-Non Finnish (NFE) AF: 0.00862 AC: 9587 AN: 1112006

Other (OTH) AF: 0.00760 AC: 459 AN: 60396

GnomAD4 genome AF: 0.00461 AC: 702 AN: 152348 Hom.: 7 Cov.: 32 AF XY: 0.00407 AC XY: 303 AN XY: 74500

African (AFR) AF: 0.00149 AC: 62 AN: 41586

American (AMR) AF: 0.00281 AC: 43 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00720 AC: 25 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4826

European-Finnish (FIN) AF: 0.00254 AC: 27 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00766 AC: 521 AN: 68028

Other (OTH) AF: 0.00614 AC: 13 AN: 2116

Alfa AF: 0.00640 Hom.: 16

Bravo AF: 0.00440

TwinsUK AF: 0.00890 AC: 33

ALSPAC AF: 0.0109 AC: 42

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00686 AC: 59

ExAC AF: 0.00521 AC: 632

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00747

EpiControl AF: 0.00705

ClinVar

Significance: Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Mar 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

LRIT3: BP4, BS2

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jun 15, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:2

Jan 30, 2015

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0066	T
Eigen	Benign	0.0066
Eigen_PC	Benign	0.0019
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.0098	T
MetaRNN	Benign	0.0043	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		1.7
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.49	N
REVEL	Benign	0.14
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.021	D
Vest4		0.12
MVP		0.15
MPC		0.14
ClinPred		0.033	T
GERP RS		2.6
Varity_R		0.069
gMVP		0.58
Mutation Taster		=97/3	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: rs35997283; hg19: chr4-110791526;