3-54918617-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_020678.4(LRTM1):c.880G>A(p.Val294Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00341 in 1,614,150 control chromosomes in the GnomAD database, including 148 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.017 ( 64 hom., cov: 31)

Exomes 𝑓: 0.0020 ( 84 hom. )

Consequence

LRTM1
NM_020678.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 3.17

Publications

7 publications found

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003754437).

BP6

Variant 3-54918617-C-T is Benign according to our data. Variant chr3-54918617-C-T is described in ClinVar as Benign. ClinVar VariationId is 784010.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0559 is higher than 0.05.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LRTM1	NM_020678.4	MANE Select	c.880G>A	p.Val294Ile	missense	Exon 3 of 3	NP_065729.1	Q9HBL6-1
CACNA2D3	NM_018398.3	MANE Select	c.2449+18749C>T		intron	N/A	NP_060868.2	Q8IZS8-1
LRTM1	NM_001304389.2		c.652G>A	p.Val218Ile	missense	Exon 3 of 3	NP_001291318.1	Q9HBL6-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LRTM1	ENST00000273286.6	TSL:1 MANE Select	c.880G>A	p.Val294Ile	missense	Exon 3 of 3	ENSP00000273286.5	Q9HBL6-1
LRTM1	ENST00000493075.1	TSL:1	c.652G>A	p.Val218Ile	missense	Exon 3 of 3	ENSP00000419772.1	Q9HBL6-2
CACNA2D3	ENST00000474759.6	TSL:1 MANE Select	c.2449+18749C>T		intron	N/A	ENSP00000419101.1	Q8IZS8-1

Frequencies

GnomAD3 genomes

AF:

0.0169

AC:

2565

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0579

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00687

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000338

Gnomad OTH

AF:

0.0129

GnomAD2 exomes

AF:

0.00454

AC:

1142

AN:

251414

AF XY:

0.00324

show subpopulations

Gnomad AFR exome

AF:

0.0605

Gnomad AMR exome

AF:

0.00260

Gnomad ASJ exome

AF:

0.000993

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000343

Gnomad OTH exome

AF:

0.00195

GnomAD4 exome

AF:

0.00201

AC:

2940

AN:

1461888

Hom.:

Cov.:

AF XY:

0.00178

AC XY:

1295

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.0637

AC:

2134

AN:

33480

American (AMR)

AF:

0.00331

AC:

148

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00134

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000267

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000210

AC:

234

AN:

1112006

Other (OTH)

AF:

0.00508

AC:

307

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

188

376

563

751

939

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

152

228

304

380

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0169

AC:

2567

AN:

152262

Hom.:

Cov.:

AF XY:

0.0162

AC XY:

1209

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.0578

AC:

2402

AN:

41540

American (AMR)

AF:

0.00687

AC:

105

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00202

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.000415

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000338

AC:

AN:

68034

Other (OTH)

AF:

0.0128

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

123

245

368

490

613

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00640

Hom.:

Bravo

AF:

0.0202

ESP6500AA

AF:

0.0583

AC:

257

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00556

AC:

675

Asia WGS

AF:

0.00577

AC:

AN:

3478

EpiCase

AF:

0.000654

EpiControl

AF:

0.000771

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Uncertain

0.97

DEOGEN2

Benign

0.0033

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.37

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.81

MetaRNN

Benign

0.0038

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.2

PhyloP100

3.2

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.48

REVEL

Benign

0.12

Sift

Benign

0.048

Sift4G

Benign

0.078

Polyphen

0.68

Vest4

0.16

MVP

0.46

MPC

0.023

ClinPred

0.029

GERP RS

1.9

Varity_R

0.047

gMVP

0.41

Mutation Taster

=83/17

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over