Genetic Variant LRRIQ3:p.Gln601Glu (chr1-74026887-G-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001105659.2(LRRIQ3):c.1801C>G(p.Gln601Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,454,898 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

LRRIQ3
NM_001105659.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.590

Publications

0 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: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.058916092).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRRIQ3	NM_001105659.2 link	c.1801C>G	p.Gln601Glu	missense_variant	Exon 8 of 8	ENST00000354431.9	NP_001099129.1	A6PVS8-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRRIQ3	ENST00000354431.9 link	c.1801C>G	p.Gln601Glu	missense_variant	Exon 8 of 8	5	NM_001105659.2	ENSP00000346414.4		A6PVS8-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1454898

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

723910

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33182

American (AMR)

AF:

0.00

AC:

AN:

44006

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25982

East Asian (EAS)

AF:

0.00

AC:

AN:

39402

South Asian (SAS)

AF:

0.00

AC:

AN:

85498

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52842

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5716

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1108200

Other (OTH)

AF:

0.0000333

AC:

AN:

60070

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.038550), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 05, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1801C>G (p.Q601E) alteration is located in exon 8 (coding exon 7) of the LRRIQ3 gene. This alteration results from a C to G substitution at nucleotide position 1801, causing the glutamine (Q) at amino acid position 601 to be replaced by a glutamic acid (E). 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

0.082

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.77

CADD

Benign

4.9

(source)

DANN

Benign

0.36

DEOGEN2

Benign

0.0012

T;T

Eigen

Benign

-0.92

Eigen_PC

Benign

-0.85

FATHMM_MKL

Benign

0.075

LIST_S2

Benign

0.48

.;T

M_CAP

Benign

0.0035

MetaRNN

Benign

0.059

T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.79

N;N

PhyloP100

0.59

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.85

N;N

REVEL

Benign

0.053

Sift

Benign

0.48

T;T

Sift4G

Benign

0.55

T;T

Polyphen

0.024

B;B

Vest4

0.074

MVP

0.048

MPC

0.0040

ClinPred

0.049

GERP RS

2.9

Varity_R

0.060

gMVP

0.0072

Mutation Taster

=98/2

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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chr1-74026887-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over