chr10-66927299-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_178011.5(LRRTM3):​c.383C>T​(p.Thr128Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,992 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

LRRTM3
NM_178011.5 missense

Scores

5
8
6

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.91
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 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.77

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
LRRTM3NM_178011.5 linkuse as main transcriptc.383C>T p.Thr128Ile missense_variant 2/3 ENST00000361320.5
CTNNA3NM_013266.4 linkuse as main transcriptc.1048-151775G>A intron_variant ENST00000433211.7
LOC101928961NR_111911.1 linkuse as main transcriptn.2718-16806G>A intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
LRRTM3ENST00000361320.5 linkuse as main transcriptc.383C>T p.Thr128Ile missense_variant 2/31 NM_178011.5 P1Q86VH5-1
CTNNA3ENST00000433211.7 linkuse as main transcriptc.1048-151775G>A intron_variant 1 NM_013266.4 P1Q9UI47-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152160
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
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
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251100
Hom.:
0
AF XY:
0.00000737
AC XY:
1
AN XY:
135746
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461832
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
727232
show subpopulations
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
AF:
0.00000657
AC:
1
AN:
152160
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74338
show subpopulations
Gnomad4 AFR
AF:
0.0000241
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:
0.00000378
ExAC
AF:
0.00000824
AC:
1

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.383C>T (p.T128I) 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 383, causing the threonine (T) at amino acid position 128 to be replaced by an isoleucine (I). 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
0.90
BayesDel_addAF
Uncertain
0.048
T
BayesDel_noAF
Uncertain
-0.070
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Benign
0.22
T
Eigen
Pathogenic
0.70
Eigen_PC
Pathogenic
0.73
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.89
D
M_CAP
Benign
0.028
D
MetaRNN
Pathogenic
0.77
D
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.1
L
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Uncertain
0.75
T
PROVEAN
Uncertain
-3.9
D
REVEL
Uncertain
0.41
Sift
Benign
0.073
T
Sift4G
Uncertain
0.0080
D
Polyphen
1.0
D
Vest4
0.82
MutPred
0.67
Gain of MoRF binding (P = 0.0697);
MVP
0.36
MPC
1.7
ClinPred
0.97
D
GERP RS
5.4
Varity_R
0.39
gMVP
0.59

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
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: rs774186675; hg19: chr10-68687057; API