6-69676271-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_018368.4(LMBRD1):​c.1510G>T​(p.Val504Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000868 in 1,612,140 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

LMBRD1
NM_018368.4 missense, splice_region

Scores

1
5
13
Splicing: ADA: 0.8920
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1O:1

Conservation

PhyloP100: 3.32
Variant links:
Genes affected
LMBRD1 (HGNC:23038): (LMBR1 domain containing 1) This gene encodes a lysosomal membrane protein that may be involved in the transport and metabolism of cobalamin. This protein also interacts with the large form of the hepatitis delta antigen and may be required for the nucleocytoplasmic shuttling of the hepatitis delta virus. Mutations in this gene are associated with the vitamin B12 metabolism disorder termed, homocystinuria-megaloblastic anemia complementation type F.[provided by RefSeq, Oct 2009]

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ACMG classification

Classification made for transcript

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=0.20291588).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
LMBRD1NM_018368.4 linkuse as main transcriptc.1510G>T p.Val504Leu missense_variant, splice_region_variant 16/16 ENST00000649934.3 NP_060838.3
LMBRD1NM_001363722.2 linkuse as main transcriptc.1291G>T p.Val431Leu missense_variant, splice_region_variant 16/16 NP_001350651.1
LMBRD1NM_001367271.1 linkuse as main transcriptc.1291G>T p.Val431Leu missense_variant, splice_region_variant 16/16 NP_001354200.1
LMBRD1NM_001367272.1 linkuse as main transcriptc.1291G>T p.Val431Leu missense_variant, splice_region_variant 16/16 NP_001354201.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
LMBRD1ENST00000649934.3 linkuse as main transcriptc.1510G>T p.Val504Leu missense_variant, splice_region_variant 16/16 NM_018368.4 ENSP00000497690 P2Q9NUN5-1

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152048
Hom.:
0
Cov.:
32
show subpopulations
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:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000161
AC:
4
AN:
248754
Hom.:
0
AF XY:
0.0000223
AC XY:
3
AN XY:
134578
show subpopulations
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:
0.0000356
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000685
AC:
10
AN:
1460092
Hom.:
0
Cov.:
30
AF XY:
0.0000110
AC XY:
8
AN XY:
726326
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000900
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152048
Hom.:
0
Cov.:
32
AF XY:
0.0000404
AC XY:
3
AN XY:
74260
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000676
Hom.:
0
Bravo
AF:
0.0000340

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1Other:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Methylmalonic aciduria and homocystinuria type cblF Uncertain:1Other:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJun 27, 2022This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 504 of the LMBRD1 protein (p.Val504Leu). This variant is present in population databases (no rsID available, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with LMBRD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 684470). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
not provided, no classification providedphenotyping onlyGenomeConnect, ClinGen-Variant interpretted as Uncertain significance and reported on 12/09/2017 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.20
BayesDel_addAF
Benign
-0.21
T
BayesDel_noAF
Benign
-0.44
CADD
Benign
23
DANN
Uncertain
0.98
DEOGEN2
Benign
0.028
T;T;.;.;.;.;.;.;.;.;.;.;.
Eigen
Benign
-0.081
Eigen_PC
Benign
-0.023
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.90
.;D;.;.;.;.;D;.;.;.;.;.;D
M_CAP
Benign
0.018
T
MetaRNN
Benign
0.20
T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Uncertain
2.2
M;M;.;.;.;.;.;.;.;.;.;.;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.65
T
PROVEAN
Benign
-1.3
N;.;.;N;.;.;.;.;.;.;.;.;.
REVEL
Benign
0.030
Sift
Benign
0.035
D;.;.;D;.;.;.;.;.;.;.;.;.
Sift4G
Uncertain
0.039
D;.;.;D;.;.;.;.;.;.;.;.;.
Polyphen
0.31
B;B;.;.;.;.;.;.;.;.;.;.;.
Vest4
0.30
MutPred
0.31
Loss of catalytic residue at V504 (P = 0.2353);Loss of catalytic residue at V504 (P = 0.2353);.;.;.;.;.;.;.;.;.;.;.;
MVP
0.50
MPC
0.12
ClinPred
0.34
T
GERP RS
4.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
2.8
Varity_R
0.10
gMVP
0.65

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.89
dbscSNV1_RF
Benign
0.65
SpliceAI score (max)
0.50
Details are displayed if max score is > 0.2
DS_AL_spliceai
0.50
Position offset: 0

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs980145400; hg19: chr6-70386163; API