1-225402973-A-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate 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, single submitter B:1
• Conservation: PhyloP100: 0.459

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 -14 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_single_submitter, 1 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/exons	MANE	UniProt
LBR	NM_002296.4	c.*330T>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.*330T>G		3_prime_UTR_variant	14/14	1	NM_002296.4	P1
LBR	ENST00000338179.6	c.*330T>G		3_prime_UTR_variant	14/14	5		P1
LBR	ENST00000651341.1	c.*1113+231T>G		intron_variant, NMD_transcript_variant

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

Gnomad4 AFR exome AF: 0.0215

Gnomad4 AMR exome AF: 0.0275

Gnomad4 ASJ exome AF: 0.0360

Gnomad4 EAS exome AF: 0.0473

Gnomad4 SAS exome AF: 0.0649

Gnomad4 FIN exome AF: 0.0793

Gnomad4 NFE exome AF: 0.0479

Gnomad4 OTH exome AF: 0.0489

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

Gnomad4 AFR AF: 0.0209

Gnomad4 AMR AF: 0.0316

Gnomad4 ASJ AF: 0.0317

Gnomad4 EAS AF: 0.0661

Gnomad4 SAS AF: 0.0693

Gnomad4 FIN AF: 0.0885

Gnomad4 NFE AF: 0.0500

Gnomad4 OTH AF: 0.0572

Alfa AF: 0.0462 Hom.: 57

Bravo AF: 0.0377

Asia WGS AF: 0.0840 AC: 291 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
Cadd	Benign	7.7
Dann	Benign	0.88

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: rs16844841; hg19: chr1-225590675;