3-54924640-G-C

Variant names:

• chr3-54924640-G-C
• NM_020678.4:c.583C>G

Variant summary

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

The NM_020678.4(LRTM1):​c.583C>G​(p.Leu195Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: LRTM1 NM_020678.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.34

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]

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]

ACMG classification

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 rank	MANE	Protein	UniProt
LRTM1	NM_020678.4	c.583C>G	p.Leu195Val	missense_variant	Exon 2 of 3	ENST00000273286.6	NP_065729.1
CACNA2D3	NM_018398.3	c.2449+24772G>C		intron_variant	Intron 27 of 37	ENST00000474759.6	NP_060868.2
LRTM1	NM_001304389.2	c.355C>G	p.Leu119Val	missense_variant	Exon 2 of 3		NP_001291318.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRTM1	ENST00000273286.6	c.583C>G	p.Leu195Val	missense_variant	Exon 2 of 3	1	NM_020678.4	ENSP00000273286.5
CACNA2D3	ENST00000474759.6	c.2449+24772G>C		intron_variant	Intron 27 of 37	1	NM_018398.3	ENSP00000419101.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 19, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.583C>G (p.L195V) alteration is located in exon 2 (coding exon 2) of the LRTM1 gene. This alteration results from a C to G substitution at nucleotide position 583, causing the leucine (L) at amino acid position 195 to be replaced by a valine (V). 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	0.18
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.014	T;.
Eigen	Benign	0.061
Eigen_PC	Benign	0.024
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.82	T;T
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.70	D;D
MetaSVM	Uncertain	0.30	D
MutationAssessor	Uncertain	2.7	M;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.6	N;N
REVEL	Uncertain	0.38
Sift	Uncertain	0.010	D;D
Sift4G	Uncertain	0.011	D;D
Polyphen		0.98	D;.
Vest4		0.68
MutPred		0.55		Loss of sheet (P = 0.0228);.;
MVP		0.75
MPC		0.10
ClinPred		0.92	D
GERP RS		2.0
Varity_R		0.13
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: chr3-54958667;