NM_020678.4:c.625A>G

Variant names:

• chr3-54918872-T-C
• rs1327858426
• NM_020678.4:c.625A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_020678.4(LRTM1):​c.625A>G​(p.Ile209Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000387 in 1,548,756 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: LRTM1 NM_020678.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.421
• Publications: 1 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.042725593).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020678.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRTM1	NM_020678.4	MANE Select	c.625A>G	p.Ile209Val	missense	Exon 3 of 3	NP_065729.1	Q9HBL6-1
	CACNA2D3	NM_018398.3	MANE Select	c.2449+19004T>C		intron	N/A	NP_060868.2	Q8IZS8-1
	LRTM1	NM_001304389.2		c.397A>G	p.Ile133Val	missense	Exon 3 of 3	NP_001291318.1	Q9HBL6-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRTM1	ENST00000273286.6	TSL:1 MANE Select	c.625A>G	p.Ile209Val	missense	Exon 3 of 3	ENSP00000273286.5	Q9HBL6-1
	LRTM1	ENST00000493075.1	TSL:1	c.397A>G	p.Ile133Val	missense	Exon 3 of 3	ENSP00000419772.1	Q9HBL6-2
	CACNA2D3	ENST00000474759.6	TSL:1 MANE Select	c.2449+19004T>C		intron	N/A	ENSP00000419101.1	Q8IZS8-1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152166 Hom.: 0 Cov.: 31

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

GnomAD4 exome AF: 0.00000358 AC: 5 AN: 1396590 Hom.: 0 Cov.: 32 AF XY: 0.00000146 AC XY: 1 AN XY: 686578

African (AFR) AF: 0.00 AC: 0 AN: 31462

American (AMR) AF: 0.00 AC: 0 AN: 35880

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21954

East Asian (EAS) AF: 0.00 AC: 0 AN: 38942

South Asian (SAS) AF: 0.00 AC: 0 AN: 75730

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51332

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5314

European-Non Finnish (NFE) AF: 0.00000464 AC: 5 AN: 1078472

Other (OTH) AF: 0.00 AC: 0 AN: 57504

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152166 Hom.: 0 Cov.: 31 AF XY: 0.0000134 AC XY: 1 AN XY: 74354

African (AFR) AF: 0.0000241 AC: 1 AN: 41434

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	8.3
DANN	Benign	0.67
DEOGEN2	Benign	0.0020	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.47	T
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.043	T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	0.83	L
PhyloP100		0.42
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.15	N
REVEL	Benign	0.023
Sift	Benign	0.24	T
Sift4G	Benign	0.20	T
Polyphen		0.0020	B
Vest4		0.044
MutPred		0.34		Loss of helix (P = 0.1299)
MVP		0.56
MPC		0.016
ClinPred		0.10	T
GERP RS		1.1
Varity_R		0.042
gMVP		0.30
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1327858426; hg19: chr3-54952899;