NM_002296.4:c.*330T>G

Variant names:

• chr1-225402973-A-C
• rs16844841
• NM_002296.4:c.*330T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002296.4(LBR):​c.*330T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0451 in 216,304 control chromosomes in the GnomAD database, including 272 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.044 (175 hom., cov: 33)
  • Exomes 𝑓: 0.048 (97 hom.)
• Consequence: LBR NM_002296.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.459
• Publications: 5 publications found

Genes affected

LBR (HGNC:6518): (lamin B receptor) The protein encoded by this gene belongs to the ERG4/ERG24 family. It localized in the nuclear envelope inner membrane and anchors the lamina and the heterochromatin to the membrane. It may mediate interaction between chromatin and lamin B. Mutations of this gene has been associated with autosomal recessive HEM/Greenberg skeletal dysplasia. Alternative splicing occurs at this locus and two transcript variants encoding the same protein have been identified. [provided by RefSeq, Jul 2008]

LBR Gene-Disease associations (from GenCC):

• Greenberg dysplasia

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, G2P
• Pelger-Huet anomaly

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• regressive spondylometaphyseal dysplasia

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 1-225402973-A-C is Benign according to our data. Variant chr1-225402973-A-C is described in ClinVar as [Benign]. Clinvar id is 295927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0632 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LBR	NM_002296.4	c.*330T>G		3_prime_UTR_variant	Exon 14 of 14	ENST00000272163.9	NP_002287.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LBR	ENST00000272163.9	c.*330T>G		3_prime_UTR_variant	Exon 14 of 14	1	NM_002296.4	ENSP00000272163.4
LBR	ENST00000338179.6	c.*330T>G		3_prime_UTR_variant	Exon 14 of 14	5		ENSP00000339883.2
LBR	ENST00000651341.1	n.*1113+231T>G		intron_variant	Intron 14 of 14			ENSP00000499114.1
LBR	ENST00000441022.1	n.*117T>G		downstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.0436 AC: 6634 AN: 152240 Hom.: 170 Cov.: 33

Gnomad AFR AF: 0.0210

Gnomad AMI AF: 0.0318

Gnomad AMR AF: 0.0315

Gnomad ASJ AF: 0.0317

Gnomad EAS AF: 0.0659

Gnomad SAS AF: 0.0689

Gnomad FIN AF: 0.0885

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0500

Gnomad OTH AF: 0.0497

GnomAD4 exome AF: 0.0484 AC: 3096 AN: 63946 Hom.: 97 Cov.: 0 AF XY: 0.0487 AC XY: 1617 AN XY: 33206

African (AFR) AF: 0.0215 AC: 40 AN: 1860

American (AMR) AF: 0.0275 AC: 94 AN: 3416

Ashkenazi Jewish (ASJ) AF: 0.0360 AC: 75 AN: 2084

East Asian (EAS) AF: 0.0473 AC: 172 AN: 3640

South Asian (SAS) AF: 0.0649 AC: 387 AN: 5962

European-Finnish (FIN) AF: 0.0793 AC: 192 AN: 2420

Middle Eastern (MID) AF: 0.0451 AC: 13 AN: 288

European-Non Finnish (NFE) AF: 0.0479 AC: 1930 AN: 40328

Other (OTH) AF: 0.0489 AC: 193 AN: 3948

GnomAD4 genome AF: 0.0437 AC: 6655 AN: 152358 Hom.: 175 Cov.: 33 AF XY: 0.0457 AC XY: 3404 AN XY: 74506

African (AFR) AF: 0.0209 AC: 871 AN: 41590

American (AMR) AF: 0.0316 AC: 483 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0317 AC: 110 AN: 3472

East Asian (EAS) AF: 0.0661 AC: 343 AN: 5192

South Asian (SAS) AF: 0.0693 AC: 335 AN: 4832

European-Finnish (FIN) AF: 0.0885 AC: 940 AN: 10618

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0500 AC: 3403 AN: 68026

Other (OTH) AF: 0.0572 AC: 121 AN: 2116

Alfa AF: 0.0470 Hom.: 295

Bravo AF: 0.0377

Asia WGS AF: 0.0840 AC: 291 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Greenberg dysplasia Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.60
CADD	Benign	7.7
DANN	Benign	0.88
PhyloP100		0.46
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: rs16844841; hg19: chr1-225590675;