1-74041809-T-A

Position:

• chr1-74041809-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001105659.2(LRRIQ3):​c.1122A>T​(p.Lys374Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000123 in 1,461,388 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: LRRIQ3 NM_001105659.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.203

Genes affected

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

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13529432).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRRIQ3	NM_001105659.2	c.1122A>T	p.Lys374Asn	missense_variant	7/8	ENST00000354431.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRRIQ3	ENST00000354431.9	c.1122A>T	p.Lys374Asn	missense_variant	7/8	5	NM_001105659.2	P2
LRRIQ3	ENST00000395089.5	c.1122A>T	p.Lys374Asn	missense_variant	6/7	5		P2
LRRIQ3	ENST00000417067.5	c.131-14840A>T		intron_variant		2
LRRIQ3	ENST00000415760.5	c.*2585A>T		3_prime_UTR_variant, NMD_transcript_variant	9/10	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1461388 Hom.: 0 Cov.: 32 AF XY: 0.0000165 AC XY: 12 AN XY: 726998

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000162

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000828 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 14, 2023

The c.1122A>T (p.K374N) alteration is located in exon 7 (coding exon 6) of the LRRIQ3 gene. This alteration results from a A to T substitution at nucleotide position 1122, causing the lysine (K) at amino acid position 374 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	0.13
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	7.6
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0044	T;T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.073	N
LIST_S2	Benign	0.41	.;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.14	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.4	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.82	N;N
REVEL	Benign	0.035
Sift	Uncertain	0.010	D;D
Sift4G	Uncertain	0.019	D;D
Polyphen		0.93	P;P
Vest4		0.11
MutPred		0.33		Loss of methylation at K374 (P = 0.0025);Loss of methylation at K374 (P = 0.0025);
MVP		0.15
MPC		0.0085
ClinPred		0.38	T
GERP RS		1.9
Varity_R		0.10
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: rs754141533; hg19: chr1-74507493;