10-84224360-G-T

Variant summary

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

The NM_001017924.5(LRIT2):c.865C>A(p.Pro289Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P289A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LRIT2 NM_001017924.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.41

Genes affected

LRIT2 (HGNC:23443): (leucine rich repeat, Ig-like and transmembrane domains 2) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

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=0.22212937).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRIT2	NM_001017924.5	c.865C>A	p.Pro289Thr	missense_variant	2/3	ENST00000372113.7
LRIT2	NM_001284223.1	c.865C>A	p.Pro289Thr	missense_variant	2/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRIT2	ENST00000372113.7	c.865C>A	p.Pro289Thr	missense_variant	2/3	1	NM_001017924.5	P2
LRIT2	ENST00000538192.5	c.865C>A	p.Pro289Thr	missense_variant	2/4	1		A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

May 04, 2022

The c.865C>A (p.P289T) alteration is located in exon 2 (coding exon 2) of the LRIT2 gene. This alteration results from a C to A substitution at nucleotide position 865, causing the proline (P) at amino acid position 289 to be replaced by a threonine (T). 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	0.25
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	17
Dann	Uncertain	0.98
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.77	T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.22	T;T
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	1.2	L;L
MutationTaster	Benign	0.78	N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.7	N;N
REVEL	Benign	0.21
Sift	Uncertain	0.026	D;D
Sift4G	Uncertain	0.042	D;T
Polyphen		0.68	.;P
Vest4		0.19
MutPred		0.53		Loss of catalytic residue at P289 (P = 0.0463);Loss of catalytic residue at P289 (P = 0.0463);
MVP		0.47
MPC		0.0069
ClinPred		0.41	T
GERP RS		5.3
Varity_R		0.14
gMVP		0.40

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: chr10-85984116;