12-58876589-G-A

Position:

• chr12-58876589-G-A

Variant summary

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

The NM_153377.5(LRIG3):​c.2551C>T​(p.Pro851Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,822 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: LRIG3 NM_153377.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.12

Genes affected

LRIG3 (HGNC:30991): (leucine rich repeats and immunoglobulin like domains 3) Predicted to act upstream of or within otolith morphogenesis. Located in extracellular space. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRIG3	NM_153377.5	c.2551C>T	p.Pro851Ser	missense_variant	16/19	ENST00000320743.8	NP_700356.2
LRIG3	NM_001136051.3	c.2371C>T	p.Pro791Ser	missense_variant	16/19		NP_001129523.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRIG3	ENST00000320743.8	c.2551C>T	p.Pro851Ser	missense_variant	16/19	1	NM_153377.5	ENSP00000326759	P1
LRIG3	ENST00000379141.8	c.2371C>T	p.Pro791Ser	missense_variant	16/19	1		ENSP00000368436
LRIG3	ENST00000433272.6	c.*789C>T		3_prime_UTR_variant, NMD_transcript_variant	17/20	1		ENSP00000413143
LRIG3	ENST00000552646.1	n.110C>T		non_coding_transcript_exon_variant	2/3	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461822 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727214

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Jan 10, 2022

The c.2551C>T (p.P851S) alteration is located in exon 16 (coding exon 16) of the LRIG3 gene. This alteration results from a C to T substitution at nucleotide position 2551, causing the proline (P) at amino acid position 851 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	Uncertain	0.36
BayesDel_addAF	Uncertain	0.049	T
BayesDel_noAF	Benign	-0.17
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.58	.;D
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Benign	0.039	D
MetaRNN	Uncertain	0.54	D;D
MetaSVM	Uncertain	0.017	D
MutationAssessor	Uncertain	2.7	.;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-6.6	D;D
REVEL	Uncertain	0.41
Sift	Uncertain	0.020	D;D
Sift4G	Uncertain	0.013	D;D
Polyphen		1.0	D;D
Vest4		0.42
MutPred		0.43		.;Loss of sheet (P = 0.0357);
MVP		0.76
MPC		0.72
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.33
gMVP		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1870926438; hg19: chr12-59270371; COSMIC: COSV57870077; COSMIC: COSV57870077;