10-66927352-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_178011.5(LRRTM3):​c.436C>T​(p.His146Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000186 in 1,614,088 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

LRRTM3
NM_178011.5 missense

Scores

1
6
12

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.15
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 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=0.1714895).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
LRRTM3NM_178011.5 linkuse as main transcriptc.436C>T p.His146Tyr missense_variant 2/3 ENST00000361320.5 NP_821079.3
CTNNA3NM_013266.4 linkuse as main transcriptc.1048-151828G>A intron_variant ENST00000433211.7 NP_037398.2
LOC101928961NR_111911.1 linkuse as main transcriptn.2718-16859G>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.436C>T p.His146Tyr missense_variant 2/31 NM_178011.5 ENSP00000355187 P1Q86VH5-1
CTNNA3ENST00000433211.7 linkuse as main transcriptc.1048-151828G>A intron_variant 1 NM_013266.4 ENSP00000389714 P1Q9UI47-1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152208
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000482
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
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
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461880
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
727242
show subpopulations
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:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152208
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74348
show subpopulations
Gnomad4 AFR
AF:
0.0000482
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
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
Bravo
AF:
0.0000113

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 GeneticsApr 13, 2022The c.436C>T (p.H146Y) alteration is located in exon 2 (coding exon 2) of the LRRTM3 gene. This alteration results from a C to T substitution at nucleotide position 436, causing the histidine (H) at amino acid position 146 to be replaced by a tyrosine (Y). 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
0.086
BayesDel_addAF
Benign
-0.21
T
BayesDel_noAF
Benign
-0.54
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Benign
0.013
T
Eigen
Benign
0.049
Eigen_PC
Uncertain
0.26
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.97
D
M_CAP
Benign
0.0086
T
MetaRNN
Benign
0.17
T
MetaSVM
Benign
-0.94
T
MutationAssessor
Benign
0.61
N
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Uncertain
0.71
T
PROVEAN
Benign
-0.68
N
REVEL
Benign
0.056
Sift
Uncertain
0.0050
D
Sift4G
Uncertain
0.0090
D
Polyphen
0.027
B
Vest4
0.29
MutPred
0.28
Loss of disorder (P = 0.055);
MVP
0.082
MPC
0.85
ClinPred
0.83
D
GERP RS
5.4
Varity_R
0.21
gMVP
0.25

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

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

Other links and lift over

dbSNP: rs1436744091; hg19: chr10-68687110; API