rs2230419

Positions:

• chr1-225419442-C-A
• chr1-225419442-C-G
• chr1-225419442-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002296.4(LBR):​c.461G>T​(p.Ser154Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign 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. S154N) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: LBR NM_002296.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.167

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_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.041336507).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LBR	NM_002296.4	c.461G>T	p.Ser154Ile	missense_variant	5/14	ENST00000272163.9	NP_002287.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LBR	ENST00000272163.9	c.461G>T	p.Ser154Ile	missense_variant	5/14	1	NM_002296.4	ENSP00000272163	P1
LBR	ENST00000338179.6	c.461G>T	p.Ser154Ile	missense_variant	5/14	5		ENSP00000339883	P1
LBR	ENST00000425080.1	c.461G>T	p.Ser154Ile	missense_variant	5/5	3		ENSP00000388059
LBR	ENST00000651341.1	c.461G>T	p.Ser154Ile	missense_variant, NMD_transcript_variant	5/15			ENSP00000499114

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.017	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	0.030
DANN	Benign	0.43
DEOGEN2	Benign	0.30	T;T;T
Eigen	Benign	-2.3
Eigen_PC	Benign	-2.3
FATHMM_MKL	Benign	0.068	N
LIST_S2	Benign	0.092	.;T;T
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.041	T;T;T
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	-1.6	N;N;.
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.010	N;N;N
REVEL	Benign	0.24
Sift	Benign	0.39	T;T;T
Sift4G	Benign	0.49	T;T;.
Polyphen		0.0	B;B;B
Vest4		0.038
MutPred		0.26		Loss of phosphorylation at S154 (P = 0.0467);Loss of phosphorylation at S154 (P = 0.0467);Loss of phosphorylation at S154 (P = 0.0467);
MVP		0.36
MPC		0.12
ClinPred		0.029	T
GERP RS		-8.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.043
gMVP		0.26

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: rs2230419; hg19: chr1-225607144;