rs112582692

chr1-225412467-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002296.4(LBR):c.1071G>A(p.Ser357=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0485 in 1,613,868 control chromosomes in the GnomAD database, including 2,075 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.040 (151 hom., cov: 32)
  • Exomes 𝑓: 0.049 (1924 hom.)
• Consequence: LBR NM_002296.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.75

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 1-225412467-C-T is Benign according to our data. Variant chr1-225412467-C-T is described in ClinVar as [Benign]. Clinvar id is 295936.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-225412467-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.74 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0547 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LBR	NM_002296.4	c.1071G>A	p.Ser357=	synonymous_variant	8/14	ENST00000272163.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LBR	ENST00000272163.9	c.1071G>A	p.Ser357=	synonymous_variant	8/14	1	NM_002296.4	P1
LBR	ENST00000338179.6	c.1071G>A	p.Ser357=	synonymous_variant	8/14	5		P1
LBR	ENST00000651341.1	c.1071G>A	p.Ser357=	synonymous_variant, NMD_transcript_variant	8/15

Frequencies

GnomAD3 genomes AF: 0.0401 AC: 6091 AN: 152048 Hom.: 146 Cov.: 32

Gnomad AFR AF: 0.0165

Gnomad AMI AF: 0.0318

Gnomad AMR AF: 0.0303

Gnomad ASJ AF: 0.0318

Gnomad EAS AF: 0.0233

Gnomad SAS AF: 0.0526

Gnomad FIN AF: 0.0888

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0498

Gnomad OTH AF: 0.0422

GnomAD3 exomes AF: 0.0466 AC: 11706 AN: 251400 Hom.: 353 AF XY: 0.0485 AC XY: 6593 AN XY: 135874

Gnomad AFR exome AF: 0.0159

Gnomad AMR exome AF: 0.0254

Gnomad ASJ exome AF: 0.0299

Gnomad EAS exome AF: 0.0208

Gnomad SAS exome AF: 0.0546

Gnomad FIN exome AF: 0.0855

Gnomad NFE exome AF: 0.0530

Gnomad OTH exome AF: 0.0554

GnomAD4 exome AF: 0.0493 AC: 72105 AN: 1461702 Hom.: 1924 Cov.: 34 AF XY: 0.0498 AC XY: 36187 AN XY: 727150

Gnomad4 AFR exome AF: 0.0148

Gnomad4 AMR exome AF: 0.0261

Gnomad4 ASJ exome AF: 0.0319

Gnomad4 EAS exome AF: 0.0311

Gnomad4 SAS exome AF: 0.0561

Gnomad4 FIN exome AF: 0.0830

Gnomad4 NFE exome AF: 0.0504

Gnomad4 OTH exome AF: 0.0474

GnomAD4 genome AF: 0.0402 AC: 6113 AN: 152166 Hom.: 151 Cov.: 32 AF XY: 0.0418 AC XY: 3107 AN XY: 74408

Gnomad4 AFR AF: 0.0165

Gnomad4 AMR AF: 0.0303

Gnomad4 ASJ AF: 0.0318

Gnomad4 EAS AF: 0.0234

Gnomad4 SAS AF: 0.0531

Gnomad4 FIN AF: 0.0888

Gnomad4 NFE AF: 0.0498

Gnomad4 OTH AF: 0.0498

Alfa AF: 0.0454 Hom.: 80

Bravo AF: 0.0341

Asia WGS AF: 0.0590 AC: 203 AN: 3478

EpiCase AF: 0.0490

EpiControl AF: 0.0536

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 21, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 05, 2018	- -

Greenberg dysplasia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

Connective tissue disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jul 14, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
Cadd	Benign	0.51
Dann	Benign	0.88
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs112582692; hg19: chr1-225600169; COSMIC: COSV55292221; COSMIC: COSV55292221;