1-225402534-T-A

Variant names:

• chr1-225402534-T-A
• rs75904736
• NM_002296.4:c.*769A>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The NM_002296.4(LBR):​c.*769A>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0075 in 152,718 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0075 (10 hom., cov: 33)
  • Exomes 𝑓: 0.0023 (0 hom.)
• Consequence: LBR NM_002296.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.514
• Publications: 1 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.2).
• BP6: Variant 1-225402534-T-A is Benign according to our data. Variant chr1-225402534-T-A is described in ClinVar as [Benign]. Clinvar id is 295923.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00751 (1144/152282) while in subpopulation SAS AF = 0.0172 (83/4834). AF 95% confidence interval is 0.0142. There are 10 homozygotes in GnomAd4. There are 560 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LBR	NM_002296.4	c.*769A>T		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.*769A>T		3_prime_UTR_variant	Exon 14 of 14	1	NM_002296.4	ENSP00000272163.4
LBR	ENST00000338179.6	c.*769A>T		3_prime_UTR_variant	Exon 14 of 14	5		ENSP00000339883.2
LBR	ENST00000651341.1	n.*1113+670A>T		intron_variant	Intron 14 of 14			ENSP00000499114.1

Frequencies

GnomAD3 genomes AF: 0.00742 AC: 1129 AN: 152166 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.00212

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00786

Gnomad ASJ AF: 0.0135

Gnomad EAS AF: 0.0159

Gnomad SAS AF: 0.0172

Gnomad FIN AF: 0.00906

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00853

Gnomad OTH AF: 0.0129

GnomAD4 exome AF: 0.00229 AC: 1 AN: 436 Hom.: 0 Cov.: 0 AF XY: 0.00379 AC XY: 1 AN XY: 264

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.00 AC: 0 AN: 2

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00235 AC: 1 AN: 426

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 4

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

GnomAD4 genome AF: 0.00751 AC: 1144 AN: 152282 Hom.: 10 Cov.: 33 AF XY: 0.00752 AC XY: 560 AN XY: 74462

African (AFR) AF: 0.00212 AC: 88 AN: 41580

American (AMR) AF: 0.00785 AC: 120 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0135 AC: 47 AN: 3470

East Asian (EAS) AF: 0.0160 AC: 83 AN: 5194

South Asian (SAS) AF: 0.0172 AC: 83 AN: 4834

European-Finnish (FIN) AF: 0.00906 AC: 96 AN: 10596

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00853 AC: 580 AN: 67996

Other (OTH) AF: 0.0199 AC: 42 AN: 2110

Alfa AF: 0.00720 Hom.: 0

Bravo AF: 0.00711

Asia WGS AF: 0.0350 AC: 122 AN: 3462

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Greenberg dysplasia Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: 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 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	-0.20
CADD	Benign	11
DANN	Benign	0.88
PhyloP100		0.51
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
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: rs75904736; hg19: chr1-225590236;