NM_178011.5:c.255C>A

Variant names:

• chr10-66927171-C-A
• NM_178011.5:c.255C>A

Variant summary

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

The NM_178011.5(LRRTM3):​c.255C>A​(p.Asn85Lys) 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 (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: LRRTM3 NM_178011.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.786

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]

LOC101928961 (HGNC:):

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=0.2601562).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRRTM3	NM_178011.5	c.255C>A	p.Asn85Lys	missense_variant	Exon 2 of 3	ENST00000361320.5	NP_821079.3
CTNNA3	NM_013266.4	c.1048-151647G>T		intron_variant	Intron 7 of 17	ENST00000433211.7	NP_037398.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRRTM3	ENST00000361320.5	c.255C>A	p.Asn85Lys	missense_variant	Exon 2 of 3	1	NM_178011.5	ENSP00000355187.3
CTNNA3	ENST00000433211.7	c.1048-151647G>T		intron_variant	Intron 7 of 17	1	NM_013266.4	ENSP00000389714.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 29, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.255C>A (p.N85K) alteration is located in exon 2 (coding exon 2) of the LRRTM3 gene. This alteration results from a C to A substitution at nucleotide position 255, causing the asparagine (N) at amino acid position 85 to be replaced by a lysine (K). 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	0.59
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.055	T
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.025
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.26	N
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.23
Sift	Benign	0.082	T
Sift4G	Benign	0.35	T
Polyphen		0.95	P
Vest4		0.42
MutPred		0.46		Gain of MoRF binding (P = 0.0445);
MVP		0.14
MPC		1.2
ClinPred		0.88	D
GERP RS		3.5
Varity_R		0.17
gMVP		0.41

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: chr10-68686929;