chr6-69676168-T-C

Position:

• chr6-69676168-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018368.4(LMBRD1):​c.1613A>G​(p.Tyr538Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,026 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: LMBRD1 NM_018368.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.95

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=0.19125083).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LMBRD1	NM_018368.4	c.1613A>G	p.Tyr538Cys	missense_variant	16/16	ENST00000649934.3	NP_060838.3
LMBRD1	NM_001363722.2	c.1394A>G	p.Tyr465Cys	missense_variant	16/16		NP_001350651.1
LMBRD1	NM_001367271.1	c.1394A>G	p.Tyr465Cys	missense_variant	16/16		NP_001354200.1
LMBRD1	NM_001367272.1	c.1394A>G	p.Tyr465Cys	missense_variant	16/16		NP_001354201.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LMBRD1	ENST00000649934.3	c.1613A>G	p.Tyr538Cys	missense_variant	16/16		NM_018368.4	ENSP00000497690	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000798 AC: 2 AN: 250752 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135500

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: 0.0000463

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460026 Hom.: 0 Cov.: 30 AF XY: 0.00000551 AC XY: 4 AN XY: 726374

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: 0.0000187

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Methylmalonic aciduria and homocystinuria type cblF Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 10, 2022

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 1487617). This variant has not been reported in the literature in individuals affected with LMBRD1-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.004%). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 538 of the LMBRD1 protein (p.Tyr538Cys). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Uncertain	0.038	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0082	T;T;.;.;.;.;.;.;.;.;.;.;.
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.65	.;T;.;.;.;.;T;.;.;.;.;.;T
M_CAP	Benign	0.0069	T
MetaRNN	Benign	0.19	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	0.60	T
PROVEAN	Benign	-0.27	N;.;.;N;.;.;.;.;.;.;.;.;.
REVEL	Benign	0.14
Sift	Uncertain	0.0060	D;.;.;D;.;.;.;.;.;.;.;.;.
Sift4G	Pathogenic	0.0	D;.;.;D;.;.;.;.;.;.;.;.;.
Polyphen		0.031	B;B;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.41
MutPred		0.32		Loss of phosphorylation at Y538 (P = 0.0172);Loss of phosphorylation at Y538 (P = 0.0172);.;.;.;.;.;.;.;.;.;.;.;
MVP		0.37
MPC		0.56
ClinPred		0.54	D
GERP RS		4.4
Varity_R		0.15
gMVP		0.47

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: rs982934588; hg19: chr6-70386060;