chr6-69697573-A-T

Variant names:

• chr6-69697573-A-T
• rs12648
• NM_018368.4:c.1407T>A

Variant summary

Our verdict is Benign. The variant received -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. 13/21 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
• Publications: 34 publications found

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 Gene-Disease associations (from GenCC):

• methylmalonic aciduria and homocystinuria type cblF

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, ClinGen, Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 138124.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.527 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018368.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LMBRD1	NM_018368.4	MANE Select	c.1407T>A	p.Asp469Glu	missense	Exon 14 of 16	NP_060838.3
	LMBRD1	NM_001363722.2		c.1188T>A	p.Asp396Glu	missense	Exon 14 of 16	NP_001350651.1
	LMBRD1	NM_001367271.1		c.1188T>A	p.Asp396Glu	missense	Exon 14 of 16	NP_001354200.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LMBRD1	ENST00000649934.3	MANE Select	c.1407T>A	p.Asp469Glu	missense	Exon 14 of 16	ENSP00000497690.1
	LMBRD1	ENST00000370570.6	TSL:1	c.1188T>A	p.Asp396Glu	missense	Exon 14 of 16	ENSP00000359602.1
	LMBRD1	ENST00000649011.1		c.1473T>A	p.Asp491Glu	missense	Exon 15 of 17	ENSP00000497575.1

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

GnomAD2 exomes AF: 0.394 AC: 98775 AN: 250410 AF XY: 0.402

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 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

African (AFR) AF: 0.153 AC: 5073 AN: 33224

American (AMR) AF: 0.380 AC: 16958 AN: 44630

Ashkenazi Jewish (ASJ) AF: 0.433 AC: 11248 AN: 25982

East Asian (EAS) AF: 0.545 AC: 21533 AN: 39490

South Asian (SAS) AF: 0.443 AC: 37992 AN: 85796

European-Finnish (FIN) AF: 0.348 AC: 18320 AN: 52626

Middle Eastern (MID) AF: 0.445 AC: 2551 AN: 5734

European-Non Finnish (NFE) AF: 0.396 AC: 434235 AN: 1097218

Other (OTH) AF: 0.395 AC: 23650 AN: 59810

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

African (AFR) AF: 0.160 AC: 6638 AN: 41490

American (AMR) AF: 0.379 AC: 5779 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.431 AC: 1497 AN: 3470

East Asian (EAS) AF: 0.544 AC: 2808 AN: 5166

South Asian (SAS) AF: 0.444 AC: 2142 AN: 4826

European-Finnish (FIN) AF: 0.339 AC: 3575 AN: 10560

Middle Eastern (MID) AF: 0.456 AC: 134 AN: 294

European-Non Finnish (NFE) AF: 0.405 AC: 27506 AN: 67852

Other (OTH) AF: 0.371 AC: 783 AN: 2108

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Aug 19, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:3

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 29, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.48
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.68	T
MetaRNN	Benign	0.00024	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.97	L
PhyloP100		3.4
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	0.050	N
REVEL	Benign	0.12
Sift	Benign	0.33	T
Sift4G	Benign	0.37	T
Polyphen		0.013	B
Vest4		0.068
MutPred		0.081		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
Mutation Taster		=96/4	polymorphism (auto)

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

Other links and lift over

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