1-225410144-A-G

Variant names:

• chr1-225410144-A-G
• rs1011319
• NM_002296.4:c.1314+147T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002296.4(LBR):​c.1314+147T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.816 in 1,183,924 control chromosomes in the GnomAD database, including 400,540 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.74 (44157 hom., cov: 32)
  • Exomes 𝑓: 0.83 (356383 hom.)
• Consequence: LBR NM_002296.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -5.94
• Publications: 7 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 1-225410144-A-G is Benign according to our data. Variant chr1-225410144-A-G is described in ClinVar as Benign. ClinVar VariationId is 1225790.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.935 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LBR	NM_002296.4	c.1314+147T>C		intron_variant	Intron 10 of 13	ENST00000272163.9	NP_002287.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LBR	ENST00000272163.9	c.1314+147T>C		intron_variant	Intron 10 of 13	1	NM_002296.4	ENSP00000272163.4
LBR	ENST00000338179.6	c.1314+147T>C		intron_variant	Intron 10 of 13	5		ENSP00000339883.2
LBR	ENST00000424022.2	n.207+147T>C		intron_variant	Intron 2 of 2	3
LBR	ENST00000651341.1	n.*480+147T>C		intron_variant	Intron 10 of 14			ENSP00000499114.1

Frequencies

GnomAD3 genomes AF: 0.742 AC: 112762 AN: 151986 Hom.: 44131 Cov.: 32

Gnomad AFR AF: 0.469

Gnomad AMI AF: 0.752

Gnomad AMR AF: 0.856

Gnomad ASJ AF: 0.882

Gnomad EAS AF: 0.957

Gnomad SAS AF: 0.698

Gnomad FIN AF: 0.862

Gnomad MID AF: 0.886

Gnomad NFE AF: 0.840

Gnomad OTH AF: 0.792

GnomAD4 exome AF: 0.827 AC: 853387 AN: 1031820 Hom.: 356383 AF XY: 0.823 AC XY: 434998 AN XY: 528358

African (AFR) AF: 0.460 AC: 11203 AN: 24328

American (AMR) AF: 0.873 AC: 34014 AN: 38984

Ashkenazi Jewish (ASJ) AF: 0.882 AC: 19611 AN: 22236

East Asian (EAS) AF: 0.963 AC: 34153 AN: 35478

South Asian (SAS) AF: 0.698 AC: 52211 AN: 74790

European-Finnish (FIN) AF: 0.861 AC: 32216 AN: 37402

Middle Eastern (MID) AF: 0.860 AC: 3116 AN: 3624

European-Non Finnish (NFE) AF: 0.840 AC: 629029 AN: 749246

Other (OTH) AF: 0.827 AC: 37834 AN: 45732

GnomAD4 genome AF: 0.742 AC: 112835 AN: 152104 Hom.: 44157 Cov.: 32 AF XY: 0.743 AC XY: 55275 AN XY: 74366

African (AFR) AF: 0.469 AC: 19460 AN: 41450

American (AMR) AF: 0.856 AC: 13084 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.882 AC: 3064 AN: 3472

East Asian (EAS) AF: 0.958 AC: 4951 AN: 5170

South Asian (SAS) AF: 0.698 AC: 3362 AN: 4816

European-Finnish (FIN) AF: 0.862 AC: 9138 AN: 10598

Middle Eastern (MID) AF: 0.888 AC: 261 AN: 294

European-Non Finnish (NFE) AF: 0.840 AC: 57151 AN: 68000

Other (OTH) AF: 0.796 AC: 1678 AN: 2108

Alfa AF: 0.787 Hom.: 6014

Bravo AF: 0.733

Asia WGS AF: 0.827 AC: 2877 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.026
DANN	Benign	0.28
PhyloP100		-5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1011319; hg19: chr1-225597846;