6-69697573-A-T

Position:

• chr6-69697573-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_018368.4(LMBRD1):​c.1407T>A​(p.Asp469Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.39 in 1,596,448 control chromosomes in the GnomAD database, including 125,478 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (9688 hom., cov: 32)
  • Exomes 𝑓: 0.40 (115790 hom.)
• Consequence: LMBRD1 NM_018368.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 3.44

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]

LMBRD1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.4306774E-4).
• BP6: Variant 6-69697573-A-T is Benign according to our data. Variant chr6-69697573-A-T is described in ClinVar as [Benign]. Clinvar id is 138124.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-69697573-A-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.527 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LMBRD1	NM_018368.4	c.1407T>A	p.Asp469Glu	missense_variant	14/16	ENST00000649934.3	NP_060838.3
LMBRD1	NM_001363722.2	c.1188T>A	p.Asp396Glu	missense_variant	14/16		NP_001350651.1
LMBRD1	NM_001367271.1	c.1188T>A	p.Asp396Glu	missense_variant	14/16		NP_001354200.1
LMBRD1	NM_001367272.1	c.1188T>A	p.Asp396Glu	missense_variant	14/16		NP_001354201.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LMBRD1	ENST00000649934.3	c.1407T>A	p.Asp469Glu	missense_variant	14/16		NM_018368.4	ENSP00000497690.1

Frequencies

GnomAD3 genomes AF: 0.337 AC: 51203 AN: 151820 Hom.: 9683 Cov.: 32

Gnomad AFR AF: 0.160

Gnomad AMI AF: 0.398

Gnomad AMR AF: 0.378

Gnomad ASJ AF: 0.431

Gnomad EAS AF: 0.543

Gnomad SAS AF: 0.443

Gnomad FIN AF: 0.339

Gnomad MID AF: 0.456

Gnomad NFE AF: 0.405

Gnomad OTH AF: 0.368

GnomAD3 exomes AF: 0.394 AC: 98775 AN: 250410 Hom.: 20429 AF XY: 0.402 AC XY: 54481 AN XY: 135426

Gnomad AFR exome AF: 0.152

Gnomad AMR exome AF: 0.379

Gnomad ASJ exome AF: 0.428

Gnomad EAS exome AF: 0.551

Gnomad SAS exome AF: 0.443

Gnomad FIN exome AF: 0.339

Gnomad NFE exome AF: 0.402

Gnomad OTH exome AF: 0.399

GnomAD4 exome AF: 0.396 AC: 571560 AN: 1444510 Hom.: 115790 Cov.: 28 AF XY: 0.399 AC XY: 287062 AN XY: 719688

Gnomad4 AFR exome AF: 0.153

Gnomad4 AMR exome AF: 0.380

Gnomad4 ASJ exome AF: 0.433

Gnomad4 EAS exome AF: 0.545

Gnomad4 SAS exome AF: 0.443

Gnomad4 FIN exome AF: 0.348

Gnomad4 NFE exome AF: 0.396

Gnomad4 OTH exome AF: 0.395

GnomAD4 genome AF: 0.337 AC: 51225 AN: 151938 Hom.: 9688 Cov.: 32 AF XY: 0.337 AC XY: 25050 AN XY: 74264

Gnomad4 AFR AF: 0.160

Gnomad4 AMR AF: 0.379

Gnomad4 ASJ AF: 0.431

Gnomad4 EAS AF: 0.544

Gnomad4 SAS AF: 0.444

Gnomad4 FIN AF: 0.339

Gnomad4 NFE AF: 0.405

Gnomad4 OTH AF: 0.371

Alfa AF: 0.397 Hom.: 9239

Bravo AF: 0.330

TwinsUK AF: 0.392 AC: 1455

ALSPAC AF: 0.396 AC: 1526

ESP6500AA AF: 0.155 AC: 681

ESP6500EA AF: 0.400 AC: 3437

ExAC AF: 0.392 AC: 47546

Asia WGS AF: 0.471 AC: 1637 AN: 3476

EpiCase AF: 0.409

EpiControl AF: 0.412

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Methylmalonic aciduria and homocystinuria type cblF Benign:4

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 19, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 29, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0079	T;T;.;.;.;.;.;.;.;.;.;.;.
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.48
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.68	.;T;.;.;.;.;T;.;.;.;.;.;T
MetaRNN	Benign	0.00024	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.97	L;L;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	0.050	N;.;.;N;.;.;.;.;.;.;.;.;.
REVEL	Benign	0.12
Sift	Benign	0.33	T;.;.;T;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.37	T;.;.;T;.;.;.;.;.;.;.;.;.
Polyphen		0.013	B;B;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.068
MutPred		0.081		Gain of glycosylation at P471 (P = 0.1041);Gain of glycosylation at P471 (P = 0.1041);.;.;.;.;.;.;.;.;.;.;.;
MPC		0.093
ClinPred		0.0091	T
GERP RS		2.0
Varity_R		0.037
gMVP		0.42

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: rs12648; hg19: chr6-70407465; COSMIC: COSV65296211;