6-69675763-A-G

Position:

• chr6-69675763-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_018368.4(LMBRD1):​c.*395T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00825 in 209,490 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0070 (22 hom., cov: 32)
  • Exomes 𝑓: 0.012 (18 hom.)
• Consequence: LMBRD1 NM_018368.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0840

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 6-69675763-A-G is Benign according to our data. Variant chr6-69675763-A-G is described in ClinVar as [Benign]. Clinvar id is 357764.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0722 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LMBRD1	NM_018368.4	c.*395T>C		3_prime_UTR_variant	16/16	ENST00000649934.3	NP_060838.3
LMBRD1	NM_001363722.2	c.*395T>C		3_prime_UTR_variant	16/16		NP_001350651.1
LMBRD1	NM_001367271.1	c.*395T>C		3_prime_UTR_variant	16/16		NP_001354200.1
LMBRD1	NM_001367272.1	c.*395T>C		3_prime_UTR_variant	16/16		NP_001354201.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LMBRD1	ENST00000649934.3	c.*395T>C		3_prime_UTR_variant	16/16		NM_018368.4	ENSP00000497690	P2
LMBRD1	ENST00000651675.1	c.*18+377T>C		intron_variant				ENSP00000498850
LMBRD1	ENST00000647655.1			downstream_gene_variant
LMBRD1	ENST00000648265.1			downstream_gene_variant

Frequencies

GnomAD3 genomes AF: 0.00703 AC: 1070 AN: 152180 Hom.: 22 Cov.: 32

Gnomad AFR AF: 0.00101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0785

Gnomad SAS AF: 0.0184

Gnomad FIN AF: 0.0301

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00290

Gnomad OTH AF: 0.00191

GnomAD4 exome AF: 0.0115 AC: 660 AN: 57192 Hom.: 18 Cov.: 0 AF XY: 0.0123 AC XY: 376 AN XY: 30450

Gnomad4 AFR exome AF: 0.000929

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0715

Gnomad4 SAS exome AF: 0.0202

Gnomad4 FIN exome AF: 0.0281

Gnomad4 NFE exome AF: 0.00494

Gnomad4 OTH exome AF: 0.0131

GnomAD4 genome AF: 0.00702 AC: 1069 AN: 152298 Hom.: 22 Cov.: 32 AF XY: 0.00913 AC XY: 680 AN XY: 74458

Gnomad4 AFR AF: 0.00101

Gnomad4 AMR AF: 0.000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0785

Gnomad4 SAS AF: 0.0184

Gnomad4 FIN AF: 0.0301

Gnomad4 NFE AF: 0.00290

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00526 Hom.: 1

Bravo AF: 0.00419

Asia WGS AF: 0.0380 AC: 132 AN: 3470

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Methylmalonic aciduria and homocystinuria type cblF Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.6
DANN	Benign	0.54

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs80330045; hg19: chr6-70385655;