NM_002296.4:c.1639A>G

Variant names:

• chr1-225404452-T-C
• rs587777171
• NM_002296.4:c.1639A>G

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PS3 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_002296.4(LBR):​c.1639A>G​(p.Asn547Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,852 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000915398: Functional studies showed that the p.ASn547Asp variant exhibited a considerable decrease in NADPH binding compared to wildtype in HeLa and LBR knockout cells as well as a nearly complete loss of de novo cholesterol synthesis in LBR knockout cell lines (Tsai et al. 2016" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N547S) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: LBR NM_002296.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 6.19
• 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: 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: Pathogenic. The variant received 20 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000915398: Functional studies showed that the p.ASn547Asp variant exhibited a considerable decrease in NADPH binding compared to wildtype in HeLa and LBR knockout cells as well as a nearly complete loss of de novo cholesterol synthesis in LBR knockout cell lines (Tsai et al. 2016; Turner and Schlieker 2016).
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-225404451-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 224875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 1-225404452-T-C is Pathogenic according to our data. Variant chr1-225404452-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 100900.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.1639A>G	p.Asn547Asp	missense	Exon 13 of 14	NP_002287.2
	LBR	NM_194442.3		c.1639A>G	p.Asn547Asp	missense	Exon 13 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.1639A>G	p.Asn547Asp	missense	Exon 13 of 14	ENSP00000272163.4	Q14739
	LBR	ENST00000338179.6	TSL:5	c.1639A>G	p.Asn547Asp	missense	Exon 13 of 14	ENSP00000339883.2	Q14739
	LBR	ENST00000885795.1		c.1639A>G	p.Asn547Asp	missense	Exon 13 of 14	ENSP00000555854.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251484 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461852 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727228

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111994

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Greenberg dysplasia (2)
1	-	-	Pelger-Huët anomaly (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.2	H
PhyloP100		6.2
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.96		Gain of relative solvent accessibility (P = 0.1259)
MVP		0.96
MPC		0.54
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.96
Mutation Taster		=4/96	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs587777171; hg19: chr1-225592154;