rs202192042

Variant names:

• chr1-74041242-C-A
• rs202192042
• NM_001105659.2:c.1689G>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001105659.2(LRRIQ3):​c.1689G>T​(p.Lys563Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000163 in 1,585,446 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (1 hom.)
• Consequence: LRRIQ3 NM_001105659.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.687
• Publications: 4 publications found

Genes affected

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

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.027425855).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRRIQ3	NM_001105659.2	c.1689G>T	p.Lys563Asn	missense_variant	Exon 7 of 8	ENST00000354431.9	NP_001099129.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRRIQ3	ENST00000354431.9	c.1689G>T	p.Lys563Asn	missense_variant	Exon 7 of 8	5	NM_001105659.2	ENSP00000346414.4
LRRIQ3	ENST00000395089.5	c.1689G>T	p.Lys563Asn	missense_variant	Exon 6 of 7	5		ENSP00000378524.1
LRRIQ3	ENST00000417067.5	c.131-14273G>T		intron_variant	Intron 1 of 1	2		ENSP00000390376.1
LRRIQ3	ENST00000415760.5	n.*2703+449G>T		intron_variant	Intron 9 of 9	2		ENSP00000415319.1

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 151920 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000192 AC: 44 AN: 228596 AF XY: 0.000202

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000683

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000609

Gnomad FIN exome AF: 0.0000478

Gnomad NFE exome AF: 0.000168

Gnomad OTH exome AF: 0.000367

GnomAD4 exome AF: 0.000170 AC: 243 AN: 1433408 Hom.: 1 Cov.: 30 AF XY: 0.000178 AC XY: 127 AN XY: 712124

African (AFR) AF: 0.00 AC: 0 AN: 31684

American (AMR) AF: 0.0000517 AC: 2 AN: 38672

Ashkenazi Jewish (ASJ) AF: 0.0000400 AC: 1 AN: 24984

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39456

South Asian (SAS) AF: 0.000636 AC: 51 AN: 80128

European-Finnish (FIN) AF: 0.0000567 AC: 3 AN: 52906

Middle Eastern (MID) AF: 0.00198 AC: 10 AN: 5062

European-Non Finnish (NFE) AF: 0.000148 AC: 163 AN: 1101382

Other (OTH) AF: 0.000203 AC: 12 AN: 59134

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152038 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74344

African (AFR) AF: 0.00 AC: 0 AN: 41478

American (AMR) AF: 0.000131 AC: 2 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4820

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10570

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 67952

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.000178 Hom.: 0

Bravo AF: 0.0000831

ExAC AF: 0.000224 AC: 27

Asia WGS AF: 0.000289 AC: 1 AN: 3476

EpiCase AF: 0.000384

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 28, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1689G>T (p.K563N) alteration is located in exon 7 (coding exon 6) of the LRRIQ3 gene. This alteration results from a G to T substitution at nucleotide position 1689, causing the lysine (K) at amino acid position 563 to be replaced by an asparagine (N). 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	0.26
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0025	T;T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.086	N
LIST_S2	Benign	0.46	.;T
M_CAP	Benign	0.0097	T
MetaRNN	Benign	0.027	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L;L
PhyloP100		0.69
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.5	N;N
REVEL	Benign	0.058
Sift	Uncertain	0.0090	D;D
Sift4G	Uncertain	0.019	D;D
Polyphen		0.93	P;P
Vest4		0.10
MutPred		0.15		Loss of methylation at K563 (P = 0.0427);Loss of methylation at K563 (P = 0.0427);
MVP		0.092
MPC		0.0040
ClinPred		0.043	T
GERP RS		3.9
Varity_R		0.13
gMVP		0.026
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs202192042; hg19: chr1-74506926; COSMIC: COSV100598776;