chr1-225412467-C-T

Variant names:

• chr1-225412467-C-T
• rs112582692
• NM_002296.4:c.1071G>A

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.1071G>A​(p.Ser357Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0485 in 1,613,868 control chromosomes in the GnomAD database, including 2,075 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.040 (151 hom., cov: 32)
  • Exomes 𝑓: 0.049 (1924 hom.)
• Consequence: LBR NM_002296.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.75
• Publications: 6 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=-0.59).
• BP6: Variant 1-225412467-C-T is Benign according to our data. Variant chr1-225412467-C-T is described in ClinVar as Benign. ClinVar VariationId is 295936.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.74 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0547 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LBR	NM_002296.4	MANE Select	c.1071G>A	p.Ser357Ser	synonymous	Exon 8 of 14	NP_002287.2
	LBR	NM_194442.3		c.1071G>A	p.Ser357Ser	synonymous	Exon 8 of 14	NP_919424.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LBR	ENST00000272163.9	TSL:1 MANE Select	c.1071G>A	p.Ser357Ser	synonymous	Exon 8 of 14	ENSP00000272163.4
	LBR	ENST00000338179.6	TSL:5	c.1071G>A	p.Ser357Ser	synonymous	Exon 8 of 14	ENSP00000339883.2
	LBR	ENST00000885795.1		c.1071G>A	p.Ser357Ser	synonymous	Exon 8 of 14	ENSP00000555854.1

Frequencies

GnomAD3 genomes AF: 0.0401 AC: 6091 AN: 152048 Hom.: 146 Cov.: 32

Gnomad AFR AF: 0.0165

Gnomad AMI AF: 0.0318

Gnomad AMR AF: 0.0303

Gnomad ASJ AF: 0.0318

Gnomad EAS AF: 0.0233

Gnomad SAS AF: 0.0526

Gnomad FIN AF: 0.0888

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0498

Gnomad OTH AF: 0.0422

GnomAD2 exomes AF: 0.0466 AC: 11706 AN: 251400 AF XY: 0.0485

Gnomad AFR exome AF: 0.0159

Gnomad AMR exome AF: 0.0254

Gnomad ASJ exome AF: 0.0299

Gnomad EAS exome AF: 0.0208

Gnomad FIN exome AF: 0.0855

Gnomad NFE exome AF: 0.0530

Gnomad OTH exome AF: 0.0554

GnomAD4 exome AF: 0.0493 AC: 72105 AN: 1461702 Hom.: 1924 Cov.: 34 AF XY: 0.0498 AC XY: 36187 AN XY: 727150

African (AFR) AF: 0.0148 AC: 494 AN: 33472

American (AMR) AF: 0.0261 AC: 1168 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0319 AC: 834 AN: 26134

East Asian (EAS) AF: 0.0311 AC: 1234 AN: 39700

South Asian (SAS) AF: 0.0561 AC: 4836 AN: 86252

European-Finnish (FIN) AF: 0.0830 AC: 4433 AN: 53416

Middle Eastern (MID) AF: 0.0447 AC: 256 AN: 5730

European-Non Finnish (NFE) AF: 0.0504 AC: 55991 AN: 1111898

Other (OTH) AF: 0.0474 AC: 2859 AN: 60380

GnomAD4 genome AF: 0.0402 AC: 6113 AN: 152166 Hom.: 151 Cov.: 32 AF XY: 0.0418 AC XY: 3107 AN XY: 74408

African (AFR) AF: 0.0165 AC: 687 AN: 41530

American (AMR) AF: 0.0303 AC: 464 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0318 AC: 110 AN: 3464

East Asian (EAS) AF: 0.0234 AC: 121 AN: 5180

South Asian (SAS) AF: 0.0531 AC: 256 AN: 4822

European-Finnish (FIN) AF: 0.0888 AC: 938 AN: 10566

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.0498 AC: 3384 AN: 68000

Other (OTH) AF: 0.0498 AC: 105 AN: 2108

Alfa AF: 0.0454 Hom.: 80

Bravo AF: 0.0341

Asia WGS AF: 0.0590 AC: 203 AN: 3478

EpiCase AF: 0.0490

EpiControl AF: 0.0536

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	Connective tissue disorder (1)
-	-	1	Greenberg dysplasia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	0.51
DANN	Benign	0.88
PhyloP100		-2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	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: rs112582692; hg19: chr1-225600169; COSMIC: COSV55292221; COSMIC: COSV55292221;