5-126777521-A-G

Position:

• chr5-126777521-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005573.4(LMNB1):​c.13A>G​(p.Thr5Ala) 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. T5T) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: LMNB1 NM_005573.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.50

Genes affected

LMNB1 (HGNC:6637): (lamin B1) This gene encodes one of the two B-type lamin proteins and is a component of the nuclear lamina. A duplication of this gene is associated with autosomal dominant adult-onset leukodystrophy (ADLD). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2015]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20345795).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LMNB1	NM_005573.4	c.13A>G	p.Thr5Ala	missense_variant	1/11	ENST00000261366.10
LMNB1	NM_001198557.2	c.-272+277A>G		intron_variant
LMNB1	NR_134488.1	n.899A>G		non_coding_transcript_exon_variant	1/12
LMNB1	NR_177109.1	n.386A>G		non_coding_transcript_exon_variant	1/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LMNB1	ENST00000261366.10	c.13A>G	p.Thr5Ala	missense_variant	1/11	1	NM_005573.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 21, 2021

Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.042	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	22
DANN	Benign	0.49
DEOGEN2	Uncertain	0.61	D;T;T
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.63	T;T;T
M_CAP	Pathogenic	0.97	D
MetaRNN	Benign	0.20	T;T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.8	L;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-2.1	N;.;N
REVEL	Benign	0.25
Sift	Benign	0.035	D;.;D
Sift4G	Uncertain	0.050	T;T;D
Polyphen		0.0060	B;.;.
Vest4		0.22
MutPred		0.16		Loss of glycosylation at T5 (P = 0.0019);Loss of glycosylation at T5 (P = 0.0019);Loss of glycosylation at T5 (P = 0.0019);
MVP		0.45
MPC		0.46
ClinPred		0.13	T
GERP RS		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.20
gMVP		0.36

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-126113213;