5-126777509-A-G

Position:

• chr5-126777509-A-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_005573.4(LMNB1):​c.1A>G​(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.000000839 in 1,192,072 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 8.4e-7 (0 hom.)
• Consequence: LMNB1 NM_005573.4 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.18

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 Pathogenic. Variant got 10 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LMNB1	NM_005573.4	c.1A>G	p.Met1?	start_lost	1/11	ENST00000261366.10	NP_005564.1
LMNB1	NM_001198557.2	c.-272+265A>G		intron_variant			NP_001185486.1
LMNB1	NR_134488.1	n.887A>G		non_coding_transcript_exon_variant	1/12
LMNB1	NR_177109.1	n.374A>G		non_coding_transcript_exon_variant	1/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LMNB1	ENST00000261366.10	c.1A>G	p.Met1?	start_lost	1/11	1	NM_005573.4	ENSP00000261366	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 8.39e-7 AC: 1 AN: 1192072 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 577100

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: 0.00000102

Gnomad4 OTH exome AF: 0.00

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

Jan 18, 2022

Not observed at significant frequency in large population cohorts (gnomAD); Initiation codon variant in a gene for which loss-of-function is not a known mechanism of disease; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.086	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	22
DANN	Benign	0.60
DEOGEN2	Uncertain	0.58	D;T;T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.57
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Benign	-0.53	T
MutationTaster	Benign	1.0	D;D
PROVEAN	Benign	-1.5	N;.;N
REVEL	Uncertain	0.38
Sift	Benign	0.031	D;.;D
Sift4G	Uncertain	0.0070	D;D;D
Polyphen		0.0050	B;.;.
Vest4		0.83
MutPred		0.96		Loss of MoRF binding (P = 0.1176);Loss of MoRF binding (P = 0.1176);Loss of MoRF binding (P = 0.1176);
MVP		0.85
ClinPred		0.97	D
GERP RS		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Varity_R		0.65
gMVP		0.24

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: chr5-126113201;