3-54918704-C-T

Variant names:

• chr3-54918704-C-T
• rs61735200
• NM_020678.4:c.793G>A

Variant summary

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

The NM_020678.4(LRTM1):​c.793G>A​(p.Glu265Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: LRTM1 NM_020678.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.117

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.092745095).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRTM1	NM_020678.4	c.793G>A	p.Glu265Lys	missense_variant	Exon 3 of 3	ENST00000273286.6	NP_065729.1
CACNA2D3	NM_018398.3	c.2449+18836C>T		intron_variant	Intron 27 of 37	ENST00000474759.6	NP_060868.2
LRTM1	NM_001304389.2	c.565G>A	p.Glu189Lys	missense_variant	Exon 3 of 3		NP_001291318.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRTM1	ENST00000273286.6	c.793G>A	p.Glu265Lys	missense_variant	Exon 3 of 3	1	NM_020678.4	ENSP00000273286.5
CACNA2D3	ENST00000474759.6	c.2449+18836C>T		intron_variant	Intron 27 of 37	1	NM_018398.3	ENSP00000419101.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251276 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135820

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461874 Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7 AN XY: 727236

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000989

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	5.2
DANN	Benign	0.97
DEOGEN2	Benign	0.0080	T;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.55	T;T
M_CAP	Benign	0.0068	T
MetaRNN	Benign	0.093	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M;.
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.81	N;N
REVEL	Benign	0.036
Sift	Benign	0.26	T;T
Sift4G	Benign	0.14	T;T
Polyphen		0.0020	B;.
Vest4		0.22
MutPred		0.42		Gain of ubiquitination at E265 (P = 0.0094);.;
MVP		0.26
MPC		0.019
ClinPred		0.042	T
GERP RS		0.28
Varity_R		0.051
gMVP		0.52

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

LitVar

Other links and lift over

dbSNP: rs61735200; hg19: chr3-54952731;