Variant 3-54924846-T-C details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_020678.4(LRTM1):c.377A>G(p.Glu126Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,738 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 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)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

LRTM1
NM_020678.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.76

Variant links:

Genes affected

LRTM1 (HGNC:25023): (leucine rich repeats and transmembrane domains 1) Predicted to enable Roundabout binding activity and heparin binding activity. Predicted to be involved in axon guidance and negative chemotaxis. Predicted to act upstream of or within positive regulation of synapse assembly. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

LRTM1 links:

CACNA2D3 (HGNC:15460): (calcium voltage-gated channel auxiliary subunit alpha2delta 3) This gene encodes a member of the alpha-2/delta subunit family, a protein in the voltage-dependent calcium channel complex. Calcium channels mediate the influx of calcium ions into the cell upon membrane polarization and consist of a complex of alpha-1, alpha-2/delta, beta, and gamma subunits in a 1:1:1:1 ratio. Various versions of each of these subunits exist, either expressed from similar genes or the result of alternative splicing. Research on a highly similar protein in rabbit suggests the protein described in this record is cleaved into alpha-2 and delta subunits. Alternate transcriptional splice variants of this gene have been observed but have not been thoroughly characterized. [provided by RefSeq, Jul 2008]

CACNA2D3 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
LRTM1	NM_020678.4 linkuse as main transcript	c.377A>G	p.Glu126Gly	missense_variant	2/3	ENST00000273286.6	NP_065729.1
CACNA2D3	NM_018398.3 linkuse as main transcript	c.2449+24978T>C		intron_variant		ENST00000474759.6	NP_060868.2
LRTM1	NM_001304389.2 linkuse as main transcript	c.149A>G	p.Glu50Gly	missense_variant	2/3		NP_001291318.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRTM1	ENST00000273286.6 linkuse as main transcript	c.377A>G	p.Glu126Gly	missense_variant	2/3	1	NM_020678.4	ENSP00000273286	P1	Q9HBL6-1
CACNA2D3	ENST00000474759.6 linkuse as main transcript	c.2449+24978T>C		intron_variant		1	NM_018398.3	ENSP00000419101	P1	Q8IZS8-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461738

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727128

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:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

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 submitter

clinical testing

Ambry Genetics

Mar 30, 2022

The c.377A>G (p.E126G) alteration is located in exon 2 (coding exon 2) of the LRTM1 gene. This alteration results from a A to G substitution at nucleotide position 377, causing the glutamic acid (E) at amino acid position 126 to be replaced by a glycine (G). 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

-0.031

BayesDel_noAF

Benign

-0.28

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.041

T;.

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.86

D;D

M_CAP

Benign

0.032

MetaRNN

Uncertain

0.54

D;D

MetaSVM

Benign

-0.61

MutationAssessor

Benign

1.9

M;.

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Benign

0.39

PROVEAN

Benign

-1.9

N;N

REVEL

Benign

0.15

Sift

Benign

0.26

T;T

Sift4G

Uncertain

0.044

D;D

Polyphen

0.97

D;.

Vest4

0.53

MutPred

0.28

Loss of stability (P = 0.0512);.;

MVP

0.84

MPC

0.060

ClinPred

0.93

GERP RS

6.0

Varity_R

0.43

gMVP

0.68

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over