rs200180113

Variant names:

• chr1-225411411-G-A
• rs200180113
• NM_002296.4:c.1114C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 3P and 5B. PP3_Moderate PP5 BS1_Supporting BS2

The NM_002296.4(LBR):​c.1114C>T​(p.Arg372Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000244 in 1,613,772 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R372H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00025 (2 hom.)
• Consequence: LBR NM_002296.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:3
• Conservation: PhyloP100: 7.90
• Publications: 17 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: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet, Ambry Genetics
• 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: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.862
• PP5: Variant 1-225411411-G-A is Pathogenic according to our data. Variant chr1-225411411-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 9533.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00021 (32/152324) while in subpopulation NFE AF = 0.000338 (23/68036). AF 95% confidence interval is 0.00023. There are 0 homozygotes in GnomAd4. There are 17 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR gene

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.1114C>T	p.Arg372Cys	missense	Exon 9 of 14	NP_002287.2
	LBR	NM_194442.3		c.1114C>T	p.Arg372Cys	missense	Exon 9 of 14	NP_919424.1	Q14739

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LBR	ENST00000272163.9	TSL:1 MANE Select	c.1114C>T	p.Arg372Cys	missense	Exon 9 of 14	ENSP00000272163.4	Q14739
	LBR	ENST00000338179.6	TSL:5	c.1114C>T	p.Arg372Cys	missense	Exon 9 of 14	ENSP00000339883.2	Q14739
	LBR	ENST00000885795.1		c.1114C>T	p.Arg372Cys	missense	Exon 9 of 14	ENSP00000555854.1

Frequencies

GnomAD3 genomes AF: 0.000210 AC: 32 AN: 152206 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000254 AC: 64 AN: 251478 AF XY: 0.000258

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.000462

Gnomad NFE exome AF: 0.000378

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000248 AC: 362 AN: 1461448 Hom.: 2 Cov.: 30 AF XY: 0.000260 AC XY: 189 AN XY: 727094

African (AFR) AF: 0.0000598 AC: 2 AN: 33468

American (AMR) AF: 0.0000671 AC: 3 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39698

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86252

European-Finnish (FIN) AF: 0.000243 AC: 13 AN: 53416

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5766

European-Non Finnish (NFE) AF: 0.000281 AC: 312 AN: 1111616

Other (OTH) AF: 0.000232 AC: 14 AN: 60374

GnomAD4 genome AF: 0.000210 AC: 32 AN: 152324 Hom.: 0 Cov.: 33 AF XY: 0.000228 AC XY: 17 AN XY: 74482

African (AFR) AF: 0.0000722 AC: 3 AN: 41564

American (AMR) AF: 0.000131 AC: 2 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000338 AC: 23 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000384 Hom.: 0

Bravo AF: 0.000181

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000222 AC: 27

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	-	-	Reynolds syndrome (2)
-	1	-	Greenberg dysplasia (1)
-	1	-	Greenberg dysplasia;C4747922:Regressive spondylometaphyseal dysplasia (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		7.9
PrimateAI	Benign	0.36	T
PROVEAN	Pathogenic	-5.8	D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.69
MVP		0.93
MPC		0.57
ClinPred		0.53	D
GERP RS		6.2
Varity_R		0.73
gMVP		0.72
Mutation Taster		=7/93	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs200180113; hg19: chr1-225599113; COSMIC: COSV55287419;