rs3214021

Variant names:

• chr6-69676428-C-T
• rs3214021
• NM_018368.4:c.1509+22G>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.1509+22G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.399 in 1,599,476 control chromosomes in the GnomAD database, including 129,440 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 (10557 hom., cov: 31)
  • Exomes 𝑓: 0.40 (118883 hom.)
• Consequence: LMBRD1 NM_018368.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.0240
• Publications: 7 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=-0.87).
• BP6: Variant 6-69676428-C-T is Benign according to our data. Variant chr6-69676428-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 261024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.526 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LMBRD1	NM_018368.4	c.1509+22G>A		intron_variant	Intron 15 of 15	ENST00000649934.3	NP_060838.3
LMBRD1	NM_001363722.2	c.1290+22G>A		intron_variant	Intron 15 of 15		NP_001350651.1
LMBRD1	NM_001367271.1	c.1290+22G>A		intron_variant	Intron 15 of 15		NP_001354200.1
LMBRD1	NM_001367272.1	c.1290+22G>A		intron_variant	Intron 15 of 15		NP_001354201.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LMBRD1	ENST00000649934.3	c.1509+22G>A		intron_variant	Intron 15 of 15		NM_018368.4	ENSP00000497690.1

Frequencies

GnomAD3 genomes AF: 0.363 AC: 55037 AN: 151798 Hom.: 10549 Cov.: 31

Gnomad AFR AF: 0.238

Gnomad AMI AF: 0.399

Gnomad AMR AF: 0.391

Gnomad ASJ AF: 0.443

Gnomad EAS AF: 0.542

Gnomad SAS AF: 0.445

Gnomad FIN AF: 0.343

Gnomad MID AF: 0.471

Gnomad NFE AF: 0.409

Gnomad OTH AF: 0.386

GnomAD2 exomes AF: 0.403 AC: 100647 AN: 249472 AF XY: 0.410

Gnomad AFR exome AF: 0.230

Gnomad AMR exome AF: 0.389

Gnomad ASJ exome AF: 0.439

Gnomad EAS exome AF: 0.550

Gnomad FIN exome AF: 0.342

Gnomad NFE exome AF: 0.406

Gnomad OTH exome AF: 0.406

GnomAD4 exome AF: 0.403 AC: 582655 AN: 1447558 Hom.: 118883 Cov.: 29 AF XY: 0.405 AC XY: 292179 AN XY: 721092

African (AFR) AF: 0.227 AC: 7511 AN: 33132

American (AMR) AF: 0.390 AC: 17384 AN: 44600

Ashkenazi Jewish (ASJ) AF: 0.445 AC: 11587 AN: 26020

East Asian (EAS) AF: 0.545 AC: 21520 AN: 39470

South Asian (SAS) AF: 0.445 AC: 38276 AN: 85960

European-Finnish (FIN) AF: 0.352 AC: 18739 AN: 53302

Middle Eastern (MID) AF: 0.457 AC: 2622 AN: 5740

European-Non Finnish (NFE) AF: 0.401 AC: 440728 AN: 1099442

Other (OTH) AF: 0.406 AC: 24288 AN: 59892

GnomAD4 genome AF: 0.362 AC: 55066 AN: 151918 Hom.: 10557 Cov.: 31 AF XY: 0.361 AC XY: 26819 AN XY: 74228

African (AFR) AF: 0.238 AC: 9850 AN: 41418

American (AMR) AF: 0.392 AC: 5974 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.443 AC: 1537 AN: 3472

East Asian (EAS) AF: 0.543 AC: 2810 AN: 5174

South Asian (SAS) AF: 0.446 AC: 2147 AN: 4816

European-Finnish (FIN) AF: 0.343 AC: 3615 AN: 10534

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

European-Non Finnish (NFE) AF: 0.409 AC: 27811 AN: 67940

Other (OTH) AF: 0.389 AC: 819 AN: 2106

Alfa AF: 0.392 Hom.: 3921

Bravo AF: 0.358

Asia WGS AF: 0.476 AC: 1656 AN: 3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Mar 10, 2016

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. -

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PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Methylmalonic aciduria and homocystinuria type cblF Benign:1

Aug 19, 2021

Genome-Nilou Lab

Significance: 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	-0.87
CADD	Benign	1.7
DANN	Benign	0.28
PhyloP100		-0.024
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: rs3214021; hg19: chr6-70386320; COSMIC: COSV65296527;