1-225404452-T-C

Position:

chr1-225404452-T-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong

The ENST00000272163.9(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 (★★). 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
ENST00000272163.9 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 6.19

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

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 id 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 [Likely_pathogenic]. Clinvar id is 100900.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-225404452-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LBR	NM_002296.4 linkuse as main transcript	c.1639A>G	p.Asn547Asp	missense_variant	13/14	ENST00000272163.9	NP_002287.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
LBR	ENST00000272163.9 linkuse as main transcript	c.1639A>G	p.Asn547Asp	missense_variant	13/14	1	NM_002296.4	ENSP00000272163	P1
LBR	ENST00000338179.6 linkuse as main transcript	c.1639A>G	p.Asn547Asp	missense_variant	13/14	5		ENSP00000339883	P1
LBR	ENST00000441022.1 linkuse as main transcript	n.114A>G		non_coding_transcript_exon_variant	1/2	2
LBR	ENST00000651341.1 linkuse as main transcript	c.*805A>G		3_prime_UTR_variant, NMD_transcript_variant	13/15			ENSP00000499114

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251484

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135916

show subpopulations

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 SAS 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:

AN:

1461852

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Greenberg dysplasia

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2010	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 15, 2018	The LBR c.1639A>G (p.Asn547Asp) missense variant has been reported two studies (Konstantinidou et al. 2008; Clayton et al. 2010). Konstantinidou et al. (2008) identified the variant in a homozygous state in an affected fetus born to consanguineous parents who were both shown to be carriers; a second affected fetus, although untested, was also presumed to be homozygous. Clayton et al. (2010) also identified the p.Asn547Asp variant in a heterozygous state in the consanguineous parents of an affected fetus who was not tested but was presumed to be homozygous. The p.Asn547Asp variant was absent from at least 500 control chromosomes and is reported at a frequency of 0.000009 in the European (non-Finnish) population of the Genome Aggregation Database, but this frequency is based on one allele in a region of good sequencing coverage. The variant is thus presumed to be rare. 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). Based on the collective evidence, the p.Asn547Asp variant is classified as likely pathogenic for Greenberg dysplasia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Pelger-Huët anomaly

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

May 07, 2019

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.19

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.99

D;D

Eigen

Pathogenic

0.98

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.95

.;D

M_CAP

Pathogenic

0.42

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.2

H;H

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.71

PROVEAN

Pathogenic

-4.7

D;D

REVEL

Pathogenic

0.92

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.97

MutPred

0.96

Gain of relative solvent accessibility (P = 0.1259);Gain of relative solvent accessibility (P = 0.1259);

MVP

0.96

MPC

0.54

ClinPred

1.0

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.96

gMVP

0.96

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over