6-69675817-G-A

Position:

• chr6-69675817-G-A

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.*341C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.557 in 269,806 control chromosomes in the GnomAD database, including 42,775 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.57 (25110 hom., cov: 32)
  • Exomes 𝑓: 0.54 (17665 hom.)
• Consequence: LMBRD1 NM_018368.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.23

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=-0.57).
• BP6: Variant 6-69675817-G-A is Benign according to our data. Variant chr6-69675817-G-A is described in ClinVar as [Benign]. Clinvar id is 357765.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.716 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LMBRD1	NM_018368.4	c.*341C>T		3_prime_UTR_variant	16/16	ENST00000649934.3	NP_060838.3
LMBRD1	NM_001363722.2	c.*341C>T		3_prime_UTR_variant	16/16		NP_001350651.1
LMBRD1	NM_001367271.1	c.*341C>T		3_prime_UTR_variant	16/16		NP_001354200.1
LMBRD1	NM_001367272.1	c.*341C>T		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.*341C>T		3_prime_UTR_variant	16/16		NM_018368.4	ENSP00000497690	P2

Frequencies

GnomAD3 genomes AF: 0.570 AC: 86450 AN: 151798 Hom.: 25080 Cov.: 32

Gnomad AFR AF: 0.653

Gnomad AMI AF: 0.428

Gnomad AMR AF: 0.600

Gnomad ASJ AF: 0.476

Gnomad EAS AF: 0.735

Gnomad SAS AF: 0.628

Gnomad FIN AF: 0.532

Gnomad MID AF: 0.554

Gnomad NFE AF: 0.508

Gnomad OTH AF: 0.555

GnomAD4 exome AF: 0.540 AC: 63670 AN: 117890 Hom.: 17665 Cov.: 0 AF XY: 0.547 AC XY: 34631 AN XY: 63306

Gnomad4 AFR exome AF: 0.650

Gnomad4 AMR exome AF: 0.596

Gnomad4 ASJ exome AF: 0.473

Gnomad4 EAS exome AF: 0.740

Gnomad4 SAS exome AF: 0.631

Gnomad4 FIN exome AF: 0.518

Gnomad4 NFE exome AF: 0.498

Gnomad4 OTH exome AF: 0.518

GnomAD4 genome AF: 0.570 AC: 86522 AN: 151916 Hom.: 25110 Cov.: 32 AF XY: 0.571 AC XY: 42405 AN XY: 74226

Gnomad4 AFR AF: 0.653

Gnomad4 AMR AF: 0.600

Gnomad4 ASJ AF: 0.476

Gnomad4 EAS AF: 0.735

Gnomad4 SAS AF: 0.630

Gnomad4 FIN AF: 0.532

Gnomad4 NFE AF: 0.508

Gnomad4 OTH AF: 0.560

Alfa AF: 0.515 Hom.: 34145

Bravo AF: 0.574

Asia WGS AF: 0.688 AC: 2387 AN: 3472

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 12, 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	-0.57
CADD	Benign	13
DANN	Benign	0.82

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: rs9185; hg19: chr6-70385709;