1-74041482-T-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001105659.2(LRRIQ3):c.1449A>C(p.Leu483Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0023 in 1,613,350 control chromosomes in the GnomAD database, including 74 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.012 (30 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (44 hom.)
• Consequence: LRRIQ3 NM_001105659.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.183

Genes affected

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

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0030457973).
• BP6: Variant 1-74041482-T-G is Benign according to our data. Variant chr1-74041482-T-G is described in ClinVar as [Benign]. Clinvar id is 791798.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.012 (1831/152276) while in subpopulation AFR AF= 0.0417 (1731/41560). AF 95% confidence interval is 0.04. There are 30 homozygotes in gnomad4. There are 890 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 29 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRRIQ3	NM_001105659.2	c.1449A>C	p.Leu483Phe	missense_variant	7/8	ENST00000354431.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRRIQ3	ENST00000354431.9	c.1449A>C	p.Leu483Phe	missense_variant	7/8	5	NM_001105659.2	P2
LRRIQ3	ENST00000395089.5	c.1449A>C	p.Leu483Phe	missense_variant	6/7	5		P2
LRRIQ3	ENST00000417067.5	c.131-14513A>C		intron_variant		2
LRRIQ3	ENST00000415760.5	c.*2703+209A>C		intron_variant, NMD_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.0119 AC: 1813 AN: 152158 Hom.: 29 Cov.: 32

Gnomad AFR AF: 0.0413

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00478

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: 0.0000882

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.00306 AC: 758 AN: 247816 Hom.: 19 AF XY: 0.00234 AC XY: 314 AN XY: 134420

Gnomad AFR exome AF: 0.0451

Gnomad AMR exome AF: 0.00119

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: 0.0000982

Gnomad OTH exome AF: 0.00150

GnomAD4 exome AF: 0.00128 AC: 1876 AN: 1461074 Hom.: 44 Cov.: 32 AF XY: 0.00110 AC XY: 798 AN XY: 726852

Gnomad4 AFR exome AF: 0.0470

Gnomad4 AMR exome AF: 0.00173

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000306

Gnomad4 OTH exome AF: 0.00297

GnomAD4 genome AF: 0.0120 AC: 1831 AN: 152276 Hom.: 30 Cov.: 32 AF XY: 0.0119 AC XY: 890 AN XY: 74478

Gnomad4 AFR AF: 0.0417

Gnomad4 AMR AF: 0.00471

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.00428 Hom.: 6

Bravo AF: 0.0139

ESP6500AA AF: 0.0356 AC: 129

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00380 AC: 459

Asia WGS AF: 0.00577 AC: 20 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.70
Cadd	Benign	12
Dann	Uncertain	1.0
DEOGEN2	Benign	0.055	T;T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.070	N
MetaRNN	Benign	0.0030	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.8	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.4	N;N
REVEL	Benign	0.096
Sift	Uncertain	0.027	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.98	D;D
Vest4		0.24
MutPred		0.16		Loss of stability (P = 0.1064);Loss of stability (P = 0.1064);
MVP		0.085
MPC		0.0065
ClinPred		0.012	T
GERP RS		-1.3
Varity_R		0.070
gMVP		0.040

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

Other links and lift over

dbSNP: rs17094774; hg19: chr1-74507166; COSMIC: COSV104417036;