chr6-69676215-T-A

Variant summary

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

The NM_018368.4(LMBRD1):​c.1566A>T​(p.Glu522Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

LMBRD1
NM_018368.4 missense

Scores

4
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.79
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=0.13744542).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
LMBRD1NM_018368.4 linkuse as main transcriptc.1566A>T p.Glu522Asp missense_variant 16/16 ENST00000649934.3 NP_060838.3
LMBRD1NM_001363722.2 linkuse as main transcriptc.1347A>T p.Glu449Asp missense_variant 16/16 NP_001350651.1
LMBRD1NM_001367271.1 linkuse as main transcriptc.1347A>T p.Glu449Asp missense_variant 16/16 NP_001354200.1
LMBRD1NM_001367272.1 linkuse as main transcriptc.1347A>T p.Glu449Asp 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.1566A>T p.Glu522Asp missense_variant 16/16 NM_018368.4 ENSP00000497690 P2Q9NUN5-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
32

ClinVar

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

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMar 28, 2024The c.1566A>T (p.E522D) alteration is located in exon 16 (coding exon 16) of the LMBRD1 gene. This alteration results from a A to T substitution at nucleotide position 1566, causing the glutamic acid (E) at amino acid position 522 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.15
BayesDel_addAF
Benign
-0.13
T
BayesDel_noAF
Benign
-0.42
CADD
Benign
18
DANN
Uncertain
0.98
DEOGEN2
Benign
0.017
T;T;.;.;.;.;.;.;.;.;.;.;.
Eigen
Benign
-0.33
Eigen_PC
Benign
-0.27
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Benign
0.82
.;T;.;.;.;.;T;.;.;.;.;.;T
M_CAP
Benign
0.015
T
MetaRNN
Benign
0.14
T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Uncertain
2.3
M;M;.;.;.;.;.;.;.;.;.;.;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.57
T
PROVEAN
Benign
-1.1
N;.;.;N;.;.;.;.;.;.;.;.;.
REVEL
Benign
0.12
Sift
Benign
0.24
T;.;.;T;.;.;.;.;.;.;.;.;.
Sift4G
Benign
0.21
T;.;.;T;.;.;.;.;.;.;.;.;.
Polyphen
0.35
B;B;.;.;.;.;.;.;.;.;.;.;.
Vest4
0.18
MutPred
0.27
Loss of sheet (P = 0.0126);Loss of sheet (P = 0.0126);.;.;.;.;.;.;.;.;.;.;.;
MVP
0.25
MPC
0.093
ClinPred
0.34
T
GERP RS
3.0
Varity_R
0.14
gMVP
0.32

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-70386107; API