rs80028106

Variant names:

• chr1-225402647-C-T
• rs80028106
• NM_002296.4:c.*656G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_002296.4(LBR):​c.*656G>A variant causes a 3 prime UTR change. The variant allele was found at a frequency of 0.0105 in 152,552 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (11 hom., cov: 33)
  • Exomes 𝑓: 0.012 (1 hom.)
• Consequence: LBR NM_002296.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.65
• Publications: 2 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.2).
• BP6: Variant 1-225402647-C-T is Benign according to our data. Variant chr1-225402647-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 295925.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0105 (1592/152120) while in subpopulation NFE AF = 0.0162 (1100/67970). AF 95% confidence interval is 0.0154. There are 11 homozygotes in GnomAd4. There are 728 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LBR	NM_002296.4	c.*656G>A		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.*656G>A		3_prime_UTR_variant	Exon 14 of 14	1	NM_002296.4	ENSP00000272163.4
LBR	ENST00000338179.6	c.*656G>A		3_prime_UTR_variant	Exon 14 of 14	5		ENSP00000339883.2
LBR	ENST00000651341.1	n.*1113+557G>A		intron_variant	Intron 14 of 14			ENSP00000499114.1

Frequencies

GnomAD3 genomes AF: 0.0105 AC: 1591 AN: 152002 Hom.: 11 Cov.: 33

Gnomad AFR AF: 0.00336

Gnomad AMI AF: 0.0219

Gnomad AMR AF: 0.00761

Gnomad ASJ AF: 0.0187

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00829

Gnomad FIN AF: 0.00737

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0162

Gnomad OTH AF: 0.0110

GnomAD4 exome AF: 0.0116 AC: 5 AN: 432 Hom.: 1 Cov.: 0 AF XY: 0.0115 AC XY: 3 AN XY: 260

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.0117 AC: 5 AN: 426

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 2

Other (OTH) AF: 0.00 AC: 0 AN: 4

GnomAD4 genome AF: 0.0105 AC: 1592 AN: 152120 Hom.: 11 Cov.: 33 AF XY: 0.00979 AC XY: 728 AN XY: 74350

African (AFR) AF: 0.00335 AC: 139 AN: 41510

American (AMR) AF: 0.00760 AC: 116 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.0187 AC: 65 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.00830 AC: 40 AN: 4820

European-Finnish (FIN) AF: 0.00737 AC: 78 AN: 10586

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0162 AC: 1100 AN: 67970

Other (OTH) AF: 0.0109 AC: 23 AN: 2110

Alfa AF: 0.0121 Hom.: 3

Bravo AF: 0.0102

Asia WGS AF: 0.00319 AC: 11 AN: 3464

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Greenberg dysplasia Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.20
CADD	Benign	17
DANN	Benign	0.89
PhyloP100		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Mutation Taster		=100/0	polymorphism

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: rs80028106; hg19: chr1-225590349;