3-169822430-T-G

Variant names:

• chr3-169822430-T-G
• NM_001080460.3:c.509T>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001080460.3(LRRIQ4):​c.509T>G​(p.Ile170Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: LRRIQ4 NM_001080460.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.07

Genes affected

LRRIQ4 (HGNC:34298): (leucine rich repeats and IQ motif containing 4) Predicted to enable protein serine/threonine phosphatase activity. Predicted to be involved in signal transduction. Predicted to be active in cytoplasm and intracellular membrane-bounded organelle. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.958

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRRIQ4	NM_001080460.3	c.509T>G	p.Ile170Ser	missense_variant	Exon 2 of 6	ENST00000340806.7	NP_001073929.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRRIQ4	ENST00000340806.7	c.509T>G	p.Ile170Ser	missense_variant	Exon 2 of 6	5	NM_001080460.3	ENSP00000342188.6
LRRIQ4	ENST00000691416.1	c.509T>G	p.Ile170Ser	missense_variant	Exon 2 of 5			ENSP00000508855.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 12, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.509T>G (p.I170S) alteration is located in exon 1 (coding exon 1) of the LRRIQ4 gene. This alteration results from a T to G substitution at nucleotide position 509, causing the isoleucine (I) at amino acid position 170 to be replaced by a serine (S). 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	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.055	T
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.78	T
M_CAP	Uncertain	0.087	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Uncertain	2.7	M
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Uncertain	0.61
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.99	D
Vest4		0.86
MutPred		0.85		Gain of disorder (P = 0.0105);
MVP		0.61
MPC		0.63
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.80
gMVP		0.75

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-169540218;