3-54918700-C-A

Variant names:

• chr3-54918700-C-A
• rs11541701
• NM_020678.4:c.797G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_020678.4(LRTM1):​c.797G>T​(p.Arg266Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000883 in 1,614,150 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0048 (5 hom., cov: 31)
  • Exomes 𝑓: 0.00048 (4 hom.)
• Consequence: LRTM1 NM_020678.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.614
• Publications: 6 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0038592517).
• BP6: Variant 3-54918700-C-A is Benign according to our data. Variant chr3-54918700-C-A is described in ClinVar as Benign. ClinVar VariationId is 791931.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00479 (730/152270) while in subpopulation AFR AF = 0.0167 (693/41558). AF 95% confidence interval is 0.0156. There are 5 homozygotes in GnomAd4. There are 351 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 gene

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.797G>T	p.Arg266Leu	missense	Exon 3 of 3	NP_065729.1	Q9HBL6-1
	CACNA2D3	NM_018398.3	MANE Select	c.2449+18832C>A		intron	N/A	NP_060868.2	Q8IZS8-1
	LRTM1	NM_001304389.2		c.569G>T	p.Arg190Leu	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.797G>T	p.Arg266Leu	missense	Exon 3 of 3	ENSP00000273286.5	Q9HBL6-1
	LRTM1	ENST00000493075.1	TSL:1	c.569G>T	p.Arg190Leu	missense	Exon 3 of 3	ENSP00000419772.1	Q9HBL6-2
	CACNA2D3	ENST00000474759.6	TSL:1 MANE Select	c.2449+18832C>A		intron	N/A	ENSP00000419101.1	Q8IZS8-1

Frequencies

GnomAD3 genomes AF: 0.00479 AC: 729 AN: 152150 Hom.: 5 Cov.: 31

Gnomad AFR AF: 0.0167

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

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: 0.000103

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00115 AC: 290 AN: 251278 AF XY: 0.000832

Gnomad AFR exome AF: 0.0169

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000476 AC: 696 AN: 1461880 Hom.: 4 Cov.: 32 AF XY: 0.000381 AC XY: 277 AN XY: 727238

African (AFR) AF: 0.0173 AC: 580 AN: 33480

American (AMR) AF: 0.000402 AC: 18 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.0000378 AC: 42 AN: 1112004

Other (OTH) AF: 0.000861 AC: 52 AN: 60396

GnomAD4 genome AF: 0.00479 AC: 730 AN: 152270 Hom.: 5 Cov.: 31 AF XY: 0.00471 AC XY: 351 AN XY: 74456

African (AFR) AF: 0.0167 AC: 693 AN: 41558

American (AMR) AF: 0.00144 AC: 22 AN: 15292

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68030

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

Alfa AF: 0.00152 Hom.: 2

Bravo AF: 0.00540

ESP6500AA AF: 0.0161 AC: 71

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00135 AC: 164

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	0.48
DANN	Benign	0.90
DEOGEN2	Benign	0.0041	T
Eigen	Benign	-0.89
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.48	T
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.8	L
PhyloP100		-0.61
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.56	N
REVEL	Benign	0.049
Sift	Benign	0.16	T
Sift4G	Benign	0.26	T
Polyphen		0.25	B
Vest4		0.063
MVP		0.38
MPC		0.017
ClinPred		0.0034	T
GERP RS		-2.3
Varity_R		0.042
gMVP		0.39
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

dbSNP: rs11541701; hg19: chr3-54952727;