6-69713847-A-G

Variant names:

• chr6-69713847-A-G
• rs2305837
• NM_018368.4:c.763-50T>C

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.763-50T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.397 in 1,599,284 control chromosomes in the GnomAD database, including 127,984 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (10455 hom., cov: 32)
  • Exomes 𝑓: 0.40 (117529 hom.)
• Consequence: LMBRD1 NM_018368.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.83
• Publications: 6 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 (BayesDel_noAF=-0.82).
• BP6: Variant 6-69713847-A-G is Benign according to our data. Variant chr6-69713847-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 261025.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.525 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LMBRD1	NM_018368.4	c.763-50T>C		intron_variant	Intron 8 of 15	ENST00000649934.3	NP_060838.3
LMBRD1	NM_001363722.2	c.544-50T>C		intron_variant	Intron 8 of 15		NP_001350651.1
LMBRD1	NM_001367271.1	c.544-50T>C		intron_variant	Intron 8 of 15		NP_001354200.1
LMBRD1	NM_001367272.1	c.544-50T>C		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.763-50T>C		intron_variant	Intron 8 of 15		NM_018368.4	ENSP00000497690.1

Frequencies

GnomAD3 genomes AF: 0.360 AC: 54723 AN: 151808 Hom.: 10448 Cov.: 32

Gnomad AFR AF: 0.237

Gnomad AMI AF: 0.398

Gnomad AMR AF: 0.391

Gnomad ASJ AF: 0.443

Gnomad EAS AF: 0.541

Gnomad SAS AF: 0.444

Gnomad FIN AF: 0.339

Gnomad MID AF: 0.475

Gnomad NFE AF: 0.407

Gnomad OTH AF: 0.384

GnomAD2 exomes AF: 0.404 AC: 98168 AN: 243216 AF XY: 0.409

Gnomad AFR exome AF: 0.232

Gnomad AMR exome AF: 0.389

Gnomad ASJ exome AF: 0.441

Gnomad EAS exome AF: 0.552

Gnomad FIN exome AF: 0.340

Gnomad NFE exome AF: 0.406

Gnomad OTH exome AF: 0.407

GnomAD4 exome AF: 0.400 AC: 579614 AN: 1447358 Hom.: 117529 Cov.: 27 AF XY: 0.403 AC XY: 290462 AN XY: 720498

African (AFR) AF: 0.226 AC: 7511 AN: 33196

American (AMR) AF: 0.389 AC: 17223 AN: 44228

Ashkenazi Jewish (ASJ) AF: 0.446 AC: 11575 AN: 25970

East Asian (EAS) AF: 0.546 AC: 21571 AN: 39512

South Asian (SAS) AF: 0.444 AC: 38049 AN: 85720

European-Finnish (FIN) AF: 0.349 AC: 18479 AN: 52986

Middle Eastern (MID) AF: 0.448 AC: 2286 AN: 5100

European-Non Finnish (NFE) AF: 0.399 AC: 438702 AN: 1100884

Other (OTH) AF: 0.405 AC: 24218 AN: 59762

GnomAD4 genome AF: 0.360 AC: 54750 AN: 151926 Hom.: 10455 Cov.: 32 AF XY: 0.359 AC XY: 26679 AN XY: 74238

African (AFR) AF: 0.237 AC: 9813 AN: 41486

American (AMR) AF: 0.391 AC: 5945 AN: 15210

Ashkenazi Jewish (ASJ) AF: 0.443 AC: 1537 AN: 3470

East Asian (EAS) AF: 0.542 AC: 2795 AN: 5158

South Asian (SAS) AF: 0.445 AC: 2141 AN: 4816

European-Finnish (FIN) AF: 0.339 AC: 3579 AN: 10560

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

European-Non Finnish (NFE) AF: 0.407 AC: 27621 AN: 67912

Other (OTH) AF: 0.387 AC: 818 AN: 2112

Alfa AF: 0.386 Hom.: 2610

Bravo AF: 0.357

Asia WGS AF: 0.476 AC: 1656 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 29, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	9.4
DANN	Benign	0.48
PhyloP100		1.8
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: rs2305837; hg19: chr6-70423739; COSMIC: COSV65299324;