1-225422182-A-G

Variant names:

• chr1-225422182-A-G
• rs1056608
• NM_002296.4:c.261T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002296.4(LBR):​c.261T>C​(p.Pro87Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.767 in 1,613,514 control chromosomes in the GnomAD database, including 482,348 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.68 (38108 hom., cov: 31)
  • Exomes 𝑓: 0.78 (444240 hom.)
• Consequence: LBR NM_002296.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.786
• Publications: 23 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 1-225422182-A-G is Benign according to our data. Variant chr1-225422182-A-G is described in ClinVar as Benign. ClinVar VariationId is 258617.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.786 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.871 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002296.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LBR	NM_002296.4	MANE Select	c.261T>C	p.Pro87Pro	synonymous	Exon 3 of 14	NP_002287.2
	LBR	NM_194442.3		c.261T>C	p.Pro87Pro	synonymous	Exon 3 of 14	NP_919424.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LBR	ENST00000272163.9	TSL:1 MANE Select	c.261T>C	p.Pro87Pro	synonymous	Exon 3 of 14	ENSP00000272163.4
	LBR	ENST00000338179.6	TSL:5	c.261T>C	p.Pro87Pro	synonymous	Exon 3 of 14	ENSP00000339883.2
	LBR	ENST00000425080.1	TSL:3	c.261T>C	p.Pro87Pro	synonymous	Exon 3 of 5	ENSP00000388059.1

Frequencies

GnomAD3 genomes AF: 0.684 AC: 103922 AN: 151922 Hom.: 38101 Cov.: 31

Gnomad AFR AF: 0.394

Gnomad AMI AF: 0.720

Gnomad AMR AF: 0.818

Gnomad ASJ AF: 0.856

Gnomad EAS AF: 0.892

Gnomad SAS AF: 0.650

Gnomad FIN AF: 0.774

Gnomad MID AF: 0.838

Gnomad NFE AF: 0.791

Gnomad OTH AF: 0.732

GnomAD2 exomes AF: 0.763 AC: 191794 AN: 251336 AF XY: 0.761

Gnomad AFR exome AF: 0.385

Gnomad AMR exome AF: 0.848

Gnomad ASJ exome AF: 0.863

Gnomad EAS exome AF: 0.897

Gnomad FIN exome AF: 0.770

Gnomad NFE exome AF: 0.787

Gnomad OTH exome AF: 0.795

GnomAD4 exome AF: 0.776 AC: 1133824 AN: 1461474 Hom.: 444240 Cov.: 56 AF XY: 0.773 AC XY: 562047 AN XY: 727020

African (AFR) AF: 0.377 AC: 12603 AN: 33472

American (AMR) AF: 0.844 AC: 37725 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.859 AC: 22454 AN: 26136

East Asian (EAS) AF: 0.908 AC: 36040 AN: 39698

South Asian (SAS) AF: 0.652 AC: 56269 AN: 86246

European-Finnish (FIN) AF: 0.775 AC: 41374 AN: 53362

Middle Eastern (MID) AF: 0.826 AC: 4640 AN: 5618

European-Non Finnish (NFE) AF: 0.788 AC: 875935 AN: 1111844

Other (OTH) AF: 0.775 AC: 46784 AN: 60374

GnomAD4 genome AF: 0.684 AC: 103960 AN: 152040 Hom.: 38108 Cov.: 31 AF XY: 0.684 AC XY: 50812 AN XY: 74300

African (AFR) AF: 0.394 AC: 16307 AN: 41430

American (AMR) AF: 0.818 AC: 12519 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.856 AC: 2973 AN: 3472

East Asian (EAS) AF: 0.893 AC: 4625 AN: 5182

South Asian (SAS) AF: 0.650 AC: 3128 AN: 4812

European-Finnish (FIN) AF: 0.774 AC: 8155 AN: 10538

Middle Eastern (MID) AF: 0.836 AC: 244 AN: 292

European-Non Finnish (NFE) AF: 0.791 AC: 53815 AN: 67992

Other (OTH) AF: 0.728 AC: 1537 AN: 2110

Alfa AF: 0.769 Hom.: 14721

Bravo AF: 0.678

Asia WGS AF: 0.747 AC: 2598 AN: 3478

EpiCase AF: 0.797

EpiControl AF: 0.795

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	Greenberg dysplasia (2)
-	-	2	not specified (2)
-	-	1	Pelger-Huët anomaly (1)
-	-	1	Reynolds syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	1.2
DANN	Benign	0.58
PhyloP100		-0.79
Mutation Taster		=78/22	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: rs1056608; hg19: chr1-225609884; COSMIC: COSV108089099; COSMIC: COSV108089099;