Genetic Variant LRRIQ3:p.Val486Ile (chr1-74041475-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001105659.2(LRRIQ3):c.1456G>A(p.Val486Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000492 in 1,613,512 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00050 ( 2 hom. )

Consequence

LRRIQ3
NM_001105659.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.155

Publications

5 publications found

Variant links:

Genes affected

LRRIQ3 (HGNC:28318): (leucine rich repeats and IQ motif containing 3)

LRRIQ3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.019911379).

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRRIQ3	NM_001105659.2 link	c.1456G>A	p.Val486Ile	missense_variant	Exon 7 of 8	ENST00000354431.9	NP_001099129.1	A6PVS8-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
LRRIQ3	ENST00000354431.9 link	c.1456G>A	p.Val486Ile	missense_variant	Exon 7 of 8	5	NM_001105659.2	ENSP00000346414.4	A6PVS8-1
LRRIQ3	ENST00000395089.5 link	c.1456G>A	p.Val486Ile	missense_variant	Exon 6 of 7	5		ENSP00000378524.1	A6PVS8-1
LRRIQ3	ENST00000417067.5 link	c.131-14506G>A		intron_variant	Intron 1 of 1	2		ENSP00000390376.1	A6PVT2
LRRIQ3	ENST00000415760.5 link	n.*2703+216G>A		intron_variant	Intron 9 of 9	2		ENSP00000415319.1	A6PVS8-2

Frequencies

GnomAD3 genomes

AF:

0.000388

AC:

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000265

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

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:

0.000662

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000278

AC:

AN:

247830

AF XY:

0.000231

show subpopulations

Gnomad AFR exome

AF:

0.000129

Gnomad AMR exome

AF:

0.0000872

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000527

Gnomad OTH exome

AF:

0.000832

GnomAD4 exome

AF:

0.000503

AC:

735

AN:

1461272

Hom.:

Cov.:

AF XY:

0.000462

AC XY:

336

AN XY:

726936

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33438

American (AMR)

AF:

0.0000672

AC:

AN:

44668

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26120

East Asian (EAS)

AF:

0.00

AC:

AN:

39664

South Asian (SAS)

AF:

0.00

AC:

AN:

86178

European-Finnish (FIN)

AF:

0.0000188

AC:

AN:

53234

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.000639

AC:

710

AN:

1111848

Other (OTH)

AF:

0.000331

AC:

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

125

166

208

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000388

AC:

AN:

152240

Hom.:

Cov.:

AF XY:

0.000269

AC XY:

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.000265

AC:

AN:

41558

American (AMR)

AF:

0.000196

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000662

AC:

AN:

67988

Other (OTH)

AF:

0.00

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000571

Hom.:

Bravo

AF:

0.000348

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000552

AC:

ESP6500EA

AF:

0.000368

AC:

ExAC

AF:

0.000298

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000382

EpiControl

AF:

0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 12, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1456G>A (p.V486I) alteration is located in exon 7 (coding exon 6) of the LRRIQ3 gene. This alteration results from a G to A substitution at nucleotide position 1456, causing the valine (V) at amino acid position 486 to be replaced by an isoleucine (I). 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

Benign

0.083

BayesDel_addAF

Benign

-0.77

BayesDel_noAF

Benign

-0.89

CADD

Benign

0.41

(source)

DANN

Benign

0.46

DEOGEN2

Benign

0.00062

T;T

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.011

LIST_S2

Benign

0.35

.;T

M_CAP

Benign

0.0038

MetaRNN

Benign

0.020

T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

0.41

N;N

PhyloP100

-0.15

PrimateAI

Benign

0.28

PROVEAN

Benign

0.17

N;N

REVEL

Benign

0.045

Sift

Benign

0.56

T;T

Sift4G

Benign

0.56

T;T

Polyphen

0.0030

B;B

Vest4

0.043

MVP

0.030

MPC

0.0045

ClinPred

0.0055

GERP RS

-3.8

Varity_R

0.019

gMVP

0.0055

Mutation Taster

=99/1

polymorphism

(source)

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

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chr1-74041475-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over