chr10-66927761-G-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_178011.5(LRRTM3):​c.845G>T​(p.Arg282Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000211 in 1,614,032 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

LRRTM3
NM_178011.5 missense

Scores

1
4
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.92
Variant links:
Genes affected
LRRTM3 (HGNC:19410): (leucine rich repeat transmembrane neuronal 3) Involved in presynapse assembly. Acts upstream of or within positive regulation of amyloid-beta formation. Is active in glutamatergic synapse. [provided by Alliance of Genome Resources, Apr 2022]
CTNNA3 (HGNC:2511): (catenin alpha 3) This gene encodes a protein that belongs to the vinculin/alpha-catenin family. The encoded protein plays a role in cell-cell adhesion in muscle cells. Mutations in this gene are associated with arrhythmogenic right ventricular dysplasia, familial 13. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2014]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.17881942).
BS2
High AC in GnomAdExome4 at 31 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
LRRTM3NM_178011.5 linkuse as main transcriptc.845G>T p.Arg282Leu missense_variant 2/3 ENST00000361320.5 NP_821079.3
CTNNA3NM_013266.4 linkuse as main transcriptc.1048-152237C>A intron_variant ENST00000433211.7 NP_037398.2
LOC101928961NR_111911.1 linkuse as main transcriptn.2718-17268C>A intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
LRRTM3ENST00000361320.5 linkuse as main transcriptc.845G>T p.Arg282Leu missense_variant 2/31 NM_178011.5 ENSP00000355187 P1Q86VH5-1
CTNNA3ENST00000433211.7 linkuse as main transcriptc.1048-152237C>A intron_variant 1 NM_013266.4 ENSP00000389714 P1Q9UI47-1

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152148
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.000576
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000478
AC:
12
AN:
251198
Hom.:
0
AF XY:
0.0000589
AC XY:
8
AN XY:
135804
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000578
Gnomad ASJ exome
AF:
0.000893
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000880
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000212
AC:
31
AN:
1461884
Hom.:
0
Cov.:
32
AF XY:
0.0000234
AC XY:
17
AN XY:
727244
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000447
Gnomad4 ASJ exome
AF:
0.000612
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000540
Gnomad4 OTH exome
AF:
0.0000662
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152148
Hom.:
0
Cov.:
32
AF XY:
0.0000404
AC XY:
3
AN XY:
74316
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000655
Gnomad4 ASJ
AF:
0.000576
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000174
Hom.:
0
Bravo
AF:
0.0000227
ExAC
AF:
0.0000576
AC:
7

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsDec 17, 2021The c.845G>T (p.R282L) alteration is located in exon 2 (coding exon 2) of the LRRTM3 gene. This alteration results from a G to T substitution at nucleotide position 845, causing the arginine (R) at amino acid position 282 to be replaced by a leucine (L). 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
0.27
BayesDel_addAF
Benign
-0.13
T
BayesDel_noAF
Benign
-0.25
CADD
Uncertain
26
DANN
Uncertain
0.98
DEOGEN2
Benign
0.0096
T
Eigen
Benign
0.074
Eigen_PC
Uncertain
0.28
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Uncertain
0.96
D
M_CAP
Benign
0.016
T
MetaRNN
Benign
0.18
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.35
N
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Pathogenic
0.81
D
PROVEAN
Benign
0.48
N
REVEL
Benign
0.17
Sift
Benign
0.26
T
Sift4G
Benign
0.24
T
Polyphen
0.20
B
Vest4
0.57
MutPred
0.35
Loss of solvent accessibility (P = 0.1077);
MVP
0.22
MPC
0.93
ClinPred
0.21
T
GERP RS
5.7
Varity_R
0.36
gMVP
0.81

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs765796649; hg19: chr10-68687519; API