rs374343844

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PM5PP3_Strong

The NM_002296.4(LBR):​c.1640A>T​(p.Asn547Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,832 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N547D) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

LBR
NM_002296.4 missense

Scores

15
3
1

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.94
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr1-225404452-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.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.99

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
LBRNM_002296.4 linkuse as main transcriptc.1640A>T p.Asn547Ile missense_variant 13/14 ENST00000272163.9 NP_002287.2 Q14739

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
LBRENST00000272163.9 linkuse as main transcriptc.1640A>T p.Asn547Ile missense_variant 13/141 NM_002296.4 ENSP00000272163.4 Q14739

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251478
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135912
show subpopulations
Gnomad AFR exome
AF:
0.0000615
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461832
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
727214
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
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:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000756
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.00000824
AC:
1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.88
BayesDel_addAF
Pathogenic
0.30
D
BayesDel_noAF
Pathogenic
0.37
CADD
Pathogenic
30
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.98
D;D
Eigen
Pathogenic
0.97
Eigen_PC
Pathogenic
0.90
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.96
.;D
M_CAP
Pathogenic
0.77
D
MetaRNN
Pathogenic
0.99
D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.9
H;H
PrimateAI
Uncertain
0.66
T
PROVEAN
Pathogenic
-8.4
D;D
REVEL
Pathogenic
0.96
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
1.0
D;D
Vest4
0.97
MVP
0.90
MPC
0.57
ClinPred
1.0
D
GERP RS
5.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.98
gMVP
0.96

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

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

Other links and lift over

dbSNP: rs374343844; hg19: chr1-225592153; API