1-225403048-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002296.4(LBR):c.*255C>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 0.111 in 480,640 control chromosomes in the GnomAD database, including 3,851 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.092 (843 hom., cov: 32)
  • Exomes 𝑓: 0.12 (3008 hom.)
• Consequence: LBR NM_002296.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.696

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 1-225403048-G-C is Benign according to our data. Variant chr1-225403048-G-C is described in ClinVar as [Benign]. Clinvar id is 295928.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.247 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LBR	NM_002296.4	c.*255C>G		3_prime_UTR_variant	14/14	ENST00000272163.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LBR	ENST00000272163.9	c.*255C>G		3_prime_UTR_variant	14/14	1	NM_002296.4	P1
LBR	ENST00000338179.6	c.*255C>G		3_prime_UTR_variant	14/14	5		P1
LBR	ENST00000651341.1	c.*1113+156C>G		intron_variant, NMD_transcript_variant
LBR	ENST00000441022.1			downstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.0917 AC: 13946 AN: 152020 Hom.: 844 Cov.: 32

Gnomad AFR AF: 0.0358

Gnomad AMI AF: 0.116

Gnomad AMR AF: 0.0703

Gnomad ASJ AF: 0.0720

Gnomad EAS AF: 0.0410

Gnomad SAS AF: 0.258

Gnomad FIN AF: 0.115

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.120

Gnomad OTH AF: 0.0813

GnomAD4 exome AF: 0.121 AC: 39586 AN: 328504 Hom.: 3008 Cov.: 0 AF XY: 0.129 AC XY: 22568 AN XY: 174866

Gnomad4 AFR exome AF: 0.0304

Gnomad4 AMR exome AF: 0.0774

Gnomad4 ASJ exome AF: 0.0737

Gnomad4 EAS exome AF: 0.0340

Gnomad4 SAS exome AF: 0.248

Gnomad4 FIN exome AF: 0.111

Gnomad4 NFE exome AF: 0.118

Gnomad4 OTH exome AF: 0.102

GnomAD4 genome AF: 0.0917 AC: 13948 AN: 152136 Hom.: 843 Cov.: 32 AF XY: 0.0948 AC XY: 7051 AN XY: 74374

Gnomad4 AFR AF: 0.0358

Gnomad4 AMR AF: 0.0702

Gnomad4 ASJ AF: 0.0720

Gnomad4 EAS AF: 0.0409

Gnomad4 SAS AF: 0.259

Gnomad4 FIN AF: 0.115

Gnomad4 NFE AF: 0.120

Gnomad4 OTH AF: 0.0795

Alfa AF: 0.0560 Hom.: 54

Bravo AF: 0.0812

Asia WGS AF: 0.124 AC: 430 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 19, 2018

- -

Greenberg dysplasia 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	-0.82
Cadd	Benign	4.8
Dann	Benign	0.77

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: rs11551874; hg19: chr1-225590750;