chr1-225404486-TAGAAGA-CTTCTAG

Variant names:

• chr1-225404486-TAGAAGA-CTTCTAG
• rs387906416
• NM_002296.4:c.1599_1605delTCTTCTAinsCTAGAAG

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1 PP5

The NM_002296.4(LBR):​c.1599_1605delTCTTCTAinsCTAGAAG​(p.LeuLeu534*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LBR NM_002296.4 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 8.09
• Publications: 2 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_pathogenic. The variant received 9 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 1-225404486-TAGAAGA-CTTCTAG is Pathogenic according to our data. Variant chr1-225404486-TAGAAGA-CTTCTAG is described in ClinVar as Pathogenic. ClinVar VariationId is 9529.Status of the report is no_assertion_criteria_provided, 0 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.1599_1605delTCTTCTAinsCTAGAAG	p.LeuLeu534*	stop_gained	N/A	NP_002287.2
	LBR	NM_194442.3		c.1599_1605delTCTTCTAinsCTAGAAG	p.LeuLeu534*	stop_gained	N/A	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.1599_1605delTCTTCTAinsCTAGAAG	p.LeuLeu534*	stop_gained	N/A	ENSP00000272163.4	Q14739
	LBR	ENST00000338179.6	TSL:5	c.1599_1605delTCTTCTAinsCTAGAAG	p.LeuLeu534*	stop_gained	N/A	ENSP00000339883.2	Q14739
	LBR	ENST00000885795.1		c.1599_1605delTCTTCTAinsCTAGAAG	p.LeuLeu534*	stop_gained	N/A	ENSP00000555854.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.1
Mutation Taster		=6/194	disease causing (fs/PTC)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs387906416; hg19: chr1-225592188;