6-69716587-C-A

Variant names:

• chr6-69716587-C-A
• rs9346333
• NM_018368.4:c.762+2369G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_018368.4(LMBRD1):​c.762+2369G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.364 in 151,854 control chromosomes in the GnomAD database, including 10,597 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.36 (10597 hom., cov: 32)
• Consequence: LMBRD1 NM_018368.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.390
• Publications: 3 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• 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 rank	MANE	Protein	UniProt
LMBRD1	NM_018368.4	c.762+2369G>T		intron_variant	Intron 8 of 15	ENST00000649934.3	NP_060838.3
LMBRD1	NM_001363722.2	c.543+2369G>T		intron_variant	Intron 8 of 15		NP_001350651.1
LMBRD1	NM_001367271.1	c.543+2369G>T		intron_variant	Intron 8 of 15		NP_001354200.1
LMBRD1	NM_001367272.1	c.543+2369G>T		intron_variant	Intron 8 of 15		NP_001354201.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LMBRD1	ENST00000649934.3	c.762+2369G>T		intron_variant	Intron 8 of 15		NM_018368.4	ENSP00000497690.1

Frequencies

GnomAD3 genomes AF: 0.364 AC: 55294 AN: 151736 Hom.: 10590 Cov.: 32

Gnomad AFR AF: 0.250

Gnomad AMI AF: 0.398

Gnomad AMR AF: 0.391

Gnomad ASJ AF: 0.443

Gnomad EAS AF: 0.543

Gnomad SAS AF: 0.445

Gnomad FIN AF: 0.340

Gnomad MID AF: 0.475

Gnomad NFE AF: 0.407

Gnomad OTH AF: 0.387

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.364 AC: 55321 AN: 151854 Hom.: 10597 Cov.: 32 AF XY: 0.363 AC XY: 26959 AN XY: 74218

African (AFR) AF: 0.250 AC: 10336 AN: 41426

American (AMR) AF: 0.391 AC: 5969 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.443 AC: 1536 AN: 3470

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

South Asian (SAS) AF: 0.445 AC: 2144 AN: 4814

European-Finnish (FIN) AF: 0.340 AC: 3569 AN: 10490

Middle Eastern (MID) AF: 0.476 AC: 140 AN: 294

European-Non Finnish (NFE) AF: 0.407 AC: 27635 AN: 67928

Other (OTH) AF: 0.390 AC: 822 AN: 2106

Alfa AF: 0.375 Hom.: 1889

Bravo AF: 0.361

Asia WGS AF: 0.475 AC: 1654 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.81
DANN	Benign	0.73
PhyloP100		-0.39
Mutation Taster		=100/0	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: rs9346333; hg19: chr6-70426479; COSMIC: COSV65299336;