1-225402647-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate 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, single submitter B:1
• Conservation: PhyloP100: 3.65

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 -12 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_single_submitter, 1 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 11 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LBR	NM_002296.4	c.*656G>A		3_prime_UTR_variant	14/14	ENST00000272163.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LBR	ENST00000272163.9	c.*656G>A		3_prime_UTR_variant	14/14	1	NM_002296.4	P1
LBR	ENST00000338179.6	c.*656G>A		3_prime_UTR_variant	14/14	5		P1
LBR	ENST00000651341.1	c.*1113+557G>A		intron_variant, NMD_transcript_variant

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

Gnomad4 FIN exome AF: 0.0117

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

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

Gnomad4 AFR AF: 0.00335

Gnomad4 AMR AF: 0.00760

Gnomad4 ASJ AF: 0.0187

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00830

Gnomad4 FIN AF: 0.00737

Gnomad4 NFE AF: 0.0162

Gnomad4 OTH AF: 0.0109

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:1

Revision: criteria provided, single submitter

Submissions by phenotype

Greenberg dysplasia Benign:1

Likely 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 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
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1

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: rs80028106; hg19: chr1-225590349;