1-225406744-TA-T

Position:

• chr1-225406744-TA-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_002296.4(LBR):​c.1402del​(p.Tyr468ThrfsTer8) variant causes a frameshift 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). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LBR NM_002296.4 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.27

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 Pathogenic. Variant got 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-225406744-TA-T is Pathogenic according to our data. Variant chr1-225406744-TA-T is described in ClinVar as [Pathogenic]. Clinvar id is 100903.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LBR	NM_002296.4	c.1402del	p.Tyr468ThrfsTer8	frameshift_variant	11/14	ENST00000272163.9	NP_002287.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LBR	ENST00000272163.9	c.1402del	p.Tyr468ThrfsTer8	frameshift_variant	11/14	1	NM_002296.4	ENSP00000272163	P1
LBR	ENST00000338179.6	c.1402del	p.Tyr468ThrfsTer8	frameshift_variant	11/14	5		ENSP00000339883	P1
LBR	ENST00000424022.2	n.295del		non_coding_transcript_exon_variant	3/3	3
LBR	ENST00000651341.1	c.*568del		3_prime_UTR_variant, NMD_transcript_variant	11/15			ENSP00000499114

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Greenberg dysplasia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 2010

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs886037655; hg19: chr1-225594446;