6-69676215-T-A

Position:

• chr6-69676215-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.79

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]

ACMG classification

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
LMBRD1	NM_018368.4	c.1566A>T	p.Glu522Asp	missense_variant	16/16	ENST00000649934.3	NP_060838.3
LMBRD1	NM_001363722.2	c.1347A>T	p.Glu449Asp	missense_variant	16/16		NP_001350651.1
LMBRD1	NM_001367271.1	c.1347A>T	p.Glu449Asp	missense_variant	16/16		NP_001354200.1
LMBRD1	NM_001367272.1	c.1347A>T	p.Glu449Asp	missense_variant	16/16		NP_001354201.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LMBRD1	ENST00000649934.3	c.1566A>T	p.Glu522Asp	missense_variant	16/16		NM_018368.4	ENSP00000497690	P2

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

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 28, 2024

The 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;