chr1-74041739-T-C

Position:

• chr1-74041739-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001105659.2(LRRIQ3):​c.1192A>G​(p.Ile398Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00487 in 1,613,678 control chromosomes in the GnomAD database, including 341 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 0.027 (182 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (159 hom.)
• Consequence: LRRIQ3 NM_001105659.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.952

Genes affected

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

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0020168126).
• BP6: Variant 1-74041739-T-C is Benign according to our data. Variant chr1-74041739-T-C is described in ClinVar as [Benign]. Clinvar id is 775562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0902 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRRIQ3	NM_001105659.2	c.1192A>G	p.Ile398Val	missense_variant	7/8	ENST00000354431.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRRIQ3	ENST00000354431.9	c.1192A>G	p.Ile398Val	missense_variant	7/8	5	NM_001105659.2	P2
LRRIQ3	ENST00000395089.5	c.1192A>G	p.Ile398Val	missense_variant	6/7	5		P2
LRRIQ3	ENST00000417067.5	c.131-14770A>G		intron_variant		2
LRRIQ3	ENST00000415760.5	c.*2655A>G		3_prime_UTR_variant, NMD_transcript_variant	9/10	2

Frequencies

GnomAD3 genomes AF: 0.0265 AC: 4033 AN: 152078 Hom.: 183 Cov.: 32

Gnomad AFR AF: 0.0926

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00892

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.0167

GnomAD3 exomes AF: 0.00631 AC: 1571 AN: 248958 Hom.: 62 AF XY: 0.00461 AC XY: 623 AN XY: 135080

Gnomad AFR exome AF: 0.0919

Gnomad AMR exome AF: 0.00290

Gnomad ASJ exome AF: 0.0000995

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.0000465

Gnomad NFE exome AF: 0.000221

Gnomad OTH exome AF: 0.00248

GnomAD4 exome AF: 0.00261 AC: 3813 AN: 1461482 Hom.: 159 Cov.: 32 AF XY: 0.00218 AC XY: 1583 AN XY: 727036

Gnomad4 AFR exome AF: 0.0941

Gnomad4 AMR exome AF: 0.00387

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000220

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.0000854

Gnomad4 OTH exome AF: 0.00571

GnomAD4 genome AF: 0.0266 AC: 4046 AN: 152196 Hom.: 182 Cov.: 32 AF XY: 0.0253 AC XY: 1883 AN XY: 74408

Gnomad4 AFR AF: 0.0926

Gnomad4 AMR AF: 0.00884

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000353

Gnomad4 OTH AF: 0.0170

Alfa AF: 0.00489 Hom.: 50

Bravo AF: 0.0298

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0921 AC: 339

ESP6500EA AF: 0.000978 AC: 8

ExAC AF: 0.00780 AC: 942

Asia WGS AF: 0.00636 AC: 22 AN: 3476

EpiCase AF: 0.000273

EpiControl AF: 0.000415

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

LRRIQ3-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 01, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.053
DANN	Benign	0.22
DEOGEN2	Benign	0.00032	T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.032	N
LIST_S2	Benign	0.23	.;T
MetaRNN	Benign	0.0020	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.25	N;N
REVEL	Benign	0.010
Sift	Benign	0.16	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0020	B;B
Vest4		0.022
MVP		0.030
MPC		0.0044
ClinPred		0.0049	T
GERP RS		-3.7
Varity_R		0.028
gMVP		0.012

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs17094779; hg19: chr1-74507423;