rs80299691

Variant names:

• chr1-225404482-A-C
• rs80299691
• NM_002296.4:c.1609T>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_002296.4(LBR):​c.1609T>G​(p.Ser537Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000893 in 1,613,984 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0041 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00056 (7 hom.)
• Consequence: LBR NM_002296.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 4.15
• Publications: 1 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.022507876).
• BP6: Variant 1-225404482-A-C is Benign according to our data. Variant chr1-225404482-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 235704.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00414 (630/152352) while in subpopulation AFR AF = 0.0145 (601/41572). AF 95% confidence interval is 0.0135. There are 2 homozygotes in GnomAd4. There are 301 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR,AD 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.1609T>G	p.Ser537Ala	missense	Exon 13 of 14	NP_002287.2
	LBR	NM_194442.3		c.1609T>G	p.Ser537Ala	missense	Exon 13 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.1609T>G	p.Ser537Ala	missense	Exon 13 of 14	ENSP00000272163.4
	LBR	ENST00000338179.6	TSL:5	c.1609T>G	p.Ser537Ala	missense	Exon 13 of 14	ENSP00000339883.2
	LBR	ENST00000885795.1		c.1609T>G	p.Ser537Ala	missense	Exon 13 of 14	ENSP00000555854.1

Frequencies

GnomAD3 genomes AF: 0.00413 AC: 629 AN: 152234 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00124 AC: 311 AN: 251354 AF XY: 0.000854

Gnomad AFR exome AF: 0.0168

Gnomad AMR exome AF: 0.000521

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000704

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.000556 AC: 812 AN: 1461632 Hom.: 7 Cov.: 31 AF XY: 0.000490 AC XY: 356 AN XY: 727144

African (AFR) AF: 0.0188 AC: 630 AN: 33472

American (AMR) AF: 0.000537 AC: 24 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: 0.000128 AC: 11 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00383 AC: 22 AN: 5746

European-Non Finnish (NFE) AF: 0.0000405 AC: 45 AN: 1111808

Other (OTH) AF: 0.00132 AC: 80 AN: 60388

GnomAD4 genome AF: 0.00414 AC: 630 AN: 152352 Hom.: 2 Cov.: 32 AF XY: 0.00404 AC XY: 301 AN XY: 74500

African (AFR) AF: 0.0145 AC: 601 AN: 41572

American (AMR) AF: 0.000915 AC: 14 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68042

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00196 Hom.: 4

Bravo AF: 0.00493

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0154 AC: 68

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00155 AC: 188

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	1	-	Connective tissue disorder (1)
-	-	1	Greenberg dysplasia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.68	T
MetaRNN	Benign	0.023	T
MetaSVM	Uncertain	0.77	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		4.2
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.62
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.99	D
Vest4		0.56
MVP		0.87
MPC		0.31
ClinPred		0.038	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.59
gMVP		0.62
Mutation Taster		=79/21	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs80299691; hg19: chr1-225592184;