3-54918617-C-T

Position:

• chr3-54918617-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000273286.6(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. 13/20 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 ENST00000273286.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.17

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 Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRTM1	NM_020678.4	c.880G>A	p.Val294Ile	missense_variant	3/3	ENST00000273286.6	NP_065729.1
CACNA2D3	NM_018398.3	c.2449+18749C>T		intron_variant		ENST00000474759.6	NP_060868.2
LRTM1	NM_001304389.2	c.652G>A	p.Val218Ile	missense_variant	3/3		NP_001291318.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRTM1	ENST00000273286.6	c.880G>A	p.Val294Ile	missense_variant	3/3	1	NM_020678.4	ENSP00000273286.5
CACNA2D3	ENST00000474759.6	c.2449+18749C>T		intron_variant		1	NM_018398.3	ENSP00000419101.1

Frequencies

GnomAD3 genomes AF: 0.0169 AC: 2565 AN: 152144 Hom.: 65 Cov.: 31

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

GnomAD3 exomes AF: 0.00454 AC: 1142 AN: 251414 Hom.: 34 AF XY: 0.00324 AC XY: 440 AN XY: 135872

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 SAS exome AF: 0.000261

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.: 84 Cov.: 32 AF XY: 0.00178 AC XY: 1295 AN XY: 727246

Gnomad4 AFR exome AF: 0.0637

Gnomad4 AMR exome AF: 0.00331

Gnomad4 ASJ exome AF: 0.00134

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000267

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000210

Gnomad4 OTH exome AF: 0.00508

GnomAD4 genome AF: 0.0169 AC: 2567 AN: 152262 Hom.: 64 Cov.: 31 AF XY: 0.0162 AC XY: 1209 AN XY: 74456

Gnomad4 AFR AF: 0.0578

Gnomad4 AMR AF: 0.00687

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000338

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.00330 Hom.: 22

Bravo AF: 0.0202

ESP6500AA AF: 0.0583 AC: 257

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00556 AC: 675

Asia WGS AF: 0.00577 AC: 20 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.000771

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 24, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	19
DANN	Uncertain	0.97
DEOGEN2	Benign	0.0033	T;.
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.37
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.81	T;T
MetaRNN	Benign	0.0038	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.48	N;N
REVEL	Benign	0.12
Sift	Benign	0.048	D;D
Sift4G	Benign	0.078	T;T
Polyphen		0.68	P;.
Vest4		0.16
MVP		0.46
MPC		0.023
ClinPred		0.029	T
GERP RS		1.9
Varity_R		0.047
gMVP		0.41

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: rs61735203; hg19: chr3-54952644; COSMIC: COSV55531337;