chr6-69676243-C-T

Variant summary

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

The NM_018368.4(LMBRD1):​c.1538G>A​(p.Cys513Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.0000118 in 1,613,178 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

LMBRD1
NM_018368.4 missense

Scores

1
8
10

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.47
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]

Genome browser will be placed here

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=0.255139).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
LMBRD1NM_018368.4 linkuse as main transcriptc.1538G>A p.Cys513Tyr missense_variant 16/16 ENST00000649934.3 NP_060838.3
LMBRD1NM_001363722.2 linkuse as main transcriptc.1319G>A p.Cys440Tyr missense_variant 16/16 NP_001350651.1
LMBRD1NM_001367271.1 linkuse as main transcriptc.1319G>A p.Cys440Tyr missense_variant 16/16 NP_001354200.1
LMBRD1NM_001367272.1 linkuse as main transcriptc.1319G>A p.Cys440Tyr missense_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.1538G>A p.Cys513Tyr missense_variant 16/16 NM_018368.4 ENSP00000497690 P2Q9NUN5-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152114
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000280
AC:
7
AN:
250394
Hom.:
0
AF XY:
0.0000443
AC XY:
6
AN XY:
135326
show subpopulations
Gnomad AFR exome
AF:
0.0000616
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000196
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000123
AC:
18
AN:
1461064
Hom.:
0
Cov.:
30
AF XY:
0.0000220
AC XY:
16
AN XY:
726830
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000197
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152114
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74292
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378
ExAC
AF:
0.0000330
AC:
4

ClinVar

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

Submissions by phenotype

Methylmalonic aciduria and homocystinuria type cblF Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingNeuberg Centre For Genomic Medicine, NCGM-The missense variant p.C513Y in LMBRD1 (NM_018368.4) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.C513Y variant is observed in 6/30,592 (0.0196%) alleles from individuals of South Asian background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.C513Y missense variant is predicted to be damaging by both SIFT and PolyPhen2. The cysteine residue at codon 513 of LMBRD1 is conserved in all mammalian species. The nucleotide c.1538 in LMBRD1 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.52
BayesDel_addAF
Benign
-0.28
T
BayesDel_noAF
Benign
-0.36
CADD
Uncertain
25
DANN
Uncertain
0.99
DEOGEN2
Benign
0.027
T;T;.;.;.;.;.;.;.;.;.;.;.
Eigen
Uncertain
0.26
Eigen_PC
Uncertain
0.33
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.90
.;D;.;.;.;.;D;.;.;.;.;.;D
M_CAP
Benign
0.020
T
MetaRNN
Benign
0.26
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
Pathogenic
0.85
D
PROVEAN
Benign
-0.96
N;.;.;N;.;.;.;.;.;.;.;.;.
REVEL
Benign
0.17
Sift
Benign
0.33
T;.;.;T;.;.;.;.;.;.;.;.;.
Sift4G
Uncertain
0.0090
D;.;.;D;.;.;.;.;.;.;.;.;.
Polyphen
0.83
P;P;.;.;.;.;.;.;.;.;.;.;.
Vest4
0.47
MutPred
0.62
Gain of ubiquitination at K518 (P = 0.0754);Gain of ubiquitination at K518 (P = 0.0754);.;.;.;.;.;.;.;.;.;.;.;
MVP
0.71
MPC
0.33
ClinPred
0.22
T
GERP RS
5.4
Varity_R
0.22
gMVP
0.80

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
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

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

Other links and lift over

dbSNP: rs754860778; hg19: chr6-70386135; API