5-126777211-G-T

Position:

• chr5-126777211-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_005573.4(LMNB1):​c.-298G>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0574 in 280,368 control chromosomes in the GnomAD database, including 513 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.055 (258 hom., cov: 33)
  • Exomes 𝑓: 0.060 (255 hom.)
• Consequence: LMNB1 NM_005573.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0470

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 5-126777211-G-T is Benign according to our data. Variant chr5-126777211-G-T is described in ClinVar as [Benign]. Clinvar id is 350609.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0728 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LMNB1	NM_005573.4	c.-298G>T		5_prime_UTR_variant	1/11	ENST00000261366.10
LMNB1	NM_001198557.2	c.-305G>T		5_prime_UTR_variant	1/11
LMNB1	NR_134488.1	n.589G>T		non_coding_transcript_exon_variant	1/12
LMNB1	NR_177109.1	n.76G>T		non_coding_transcript_exon_variant	1/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LMNB1	ENST00000261366.10	c.-298G>T		5_prime_UTR_variant	1/11	1	NM_005573.4	P1

Frequencies

GnomAD3 genomes AF: 0.0555 AC: 8431 AN: 152040 Hom.: 258 Cov.: 33

Gnomad AFR AF: 0.0284

Gnomad AMI AF: 0.134

Gnomad AMR AF: 0.0645

Gnomad ASJ AF: 0.107

Gnomad EAS AF: 0.0275

Gnomad SAS AF: 0.0797

Gnomad FIN AF: 0.0795

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0626

Gnomad OTH AF: 0.0612

GnomAD4 exome AF: 0.0599 AC: 7677 AN: 128212 Hom.: 255 Cov.: 0 AF XY: 0.0610 AC XY: 3986 AN XY: 65318

Gnomad4 AFR exome AF: 0.0304

Gnomad4 AMR exome AF: 0.0563

Gnomad4 ASJ exome AF: 0.104

Gnomad4 EAS exome AF: 0.0320

Gnomad4 SAS exome AF: 0.0782

Gnomad4 FIN exome AF: 0.0675

Gnomad4 NFE exome AF: 0.0606

Gnomad4 OTH exome AF: 0.0657

GnomAD4 genome AF: 0.0554 AC: 8426 AN: 152156 Hom.: 258 Cov.: 33 AF XY: 0.0569 AC XY: 4234 AN XY: 74388

Gnomad4 AFR AF: 0.0283

Gnomad4 AMR AF: 0.0644

Gnomad4 ASJ AF: 0.107

Gnomad4 EAS AF: 0.0274

Gnomad4 SAS AF: 0.0794

Gnomad4 FIN AF: 0.0795

Gnomad4 NFE AF: 0.0626

Gnomad4 OTH AF: 0.0606

Alfa AF: 0.0517 Hom.: 19

Bravo AF: 0.0526

Asia WGS AF: 0.0470 AC: 163 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Adult-onset autosomal dominant demyelinating leukodystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	14
DANN	Benign	0.92

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: rs111865788; hg19: chr5-126112903;