rs387906416

Positions:

• chr1-225404486-TAGAAGA-CTTCTAG

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_002296.4(LBR):​c.1599_1605delinsCTAGAAG​(p.Leu534_Leu535delinsTer) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• 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

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 11 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-225404486-TAGAAGA-CTTCTAG is Pathogenic according to our data. Variant chr1-225404486-TAGAAGA-CTTCTAG is described in ClinVar as [Pathogenic]. Clinvar id is 9529.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LBR	NM_002296.4	c.1599_1605delinsCTAGAAG	p.Leu534_Leu535delinsTer	stop_gained	13/14	ENST00000272163.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LBR	ENST00000272163.9	c.1599_1605delinsCTAGAAG	p.Leu534_Leu535delinsTer	stop_gained	13/14	1	NM_002296.4	P1
LBR	ENST00000338179.6	c.1599_1605delinsCTAGAAG	p.Leu534_Leu535delinsTer	stop_gained	13/14	5		P1
LBR	ENST00000441022.1	n.74_80delinsCTAGAAG		non_coding_transcript_exon_variant	1/2	2
LBR	ENST00000651341.1	c.*765_*771delinsCTAGAAG		3_prime_UTR_variant, NMD_transcript_variant	13/15

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

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Pelger-Huët anomaly Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 2003

- -

Greenberg dysplasia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 2003

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs387906416; hg19: chr1-225592188;