5-126836503-C-T

Variant names:

• chr5-126836503-C-T
• rs1051644
• ENST00000460265.5:n.*1088C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000460265.5(LMNB1):​n.*1088C>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.445 in 373,606 control chromosomes in the GnomAD database, including 38,250 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.41 (13743 hom., cov: 31)
  • Exomes 𝑓: 0.47 (24507 hom.)
• Consequence: LMNB1 ENST00000460265.5 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.192
• Publications: 10 publications found

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]

LMNB1 Gene-Disease associations (from GenCC):

• microcephaly 26, primary, autosomal dominant

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• adult-onset autosomal dominant demyelinating leukodystrophy

  Inheritance: AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• microcephaly

  Inheritance: AD Classification: STRONG Submitted by: Franklin by Genoox
• autosomal dominant primary microcephaly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 5-126836503-C-T is Benign according to our data. Variant chr5-126836503-C-T is described in ClinVar as Benign. ClinVar VariationId is 350623.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.537 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LMNB1	NM_005573.4	c.*239C>T		3_prime_UTR_variant	Exon 11 of 11	ENST00000261366.10	NP_005564.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LMNB1	ENST00000460265.5	n.*1088C>T		non_coding_transcript_exon_variant	Exon 12 of 12	1		ENSP00000486528.1
LMNB1	ENST00000261366.10	c.*239C>T		3_prime_UTR_variant	Exon 11 of 11	1	NM_005573.4	ENSP00000261366.5
LMNB1	ENST00000460265.5	n.*1088C>T		3_prime_UTR_variant	Exon 12 of 12	1		ENSP00000486528.1
LMNB1	ENST00000504788.5	n.1733C>T		non_coding_transcript_exon_variant	Exon 11 of 11	2

Frequencies

GnomAD3 genomes AF: 0.415 AC: 62987 AN: 151754 Hom.: 13745 Cov.: 31

Gnomad AFR AF: 0.292

Gnomad AMI AF: 0.359

Gnomad AMR AF: 0.439

Gnomad ASJ AF: 0.448

Gnomad EAS AF: 0.554

Gnomad SAS AF: 0.547

Gnomad FIN AF: 0.532

Gnomad MID AF: 0.396

Gnomad NFE AF: 0.446

Gnomad OTH AF: 0.409

GnomAD4 exome AF: 0.466 AC: 103263 AN: 221732 Hom.: 24507 Cov.: 2 AF XY: 0.465 AC XY: 52747 AN XY: 113444

African (AFR) AF: 0.299 AC: 1959 AN: 6562

American (AMR) AF: 0.466 AC: 3097 AN: 6652

Ashkenazi Jewish (ASJ) AF: 0.455 AC: 3821 AN: 8398

East Asian (EAS) AF: 0.581 AC: 11625 AN: 19996

South Asian (SAS) AF: 0.576 AC: 2045 AN: 3550

European-Finnish (FIN) AF: 0.543 AC: 9720 AN: 17902

Middle Eastern (MID) AF: 0.410 AC: 462 AN: 1128

European-Non Finnish (NFE) AF: 0.449 AC: 64140 AN: 142960

Other (OTH) AF: 0.438 AC: 6394 AN: 14584

GnomAD4 genome AF: 0.415 AC: 63005 AN: 151874 Hom.: 13743 Cov.: 31 AF XY: 0.423 AC XY: 31363 AN XY: 74166

African (AFR) AF: 0.291 AC: 12076 AN: 41432

American (AMR) AF: 0.439 AC: 6699 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.448 AC: 1555 AN: 3470

East Asian (EAS) AF: 0.554 AC: 2852 AN: 5152

South Asian (SAS) AF: 0.548 AC: 2641 AN: 4818

European-Finnish (FIN) AF: 0.532 AC: 5588 AN: 10508

Middle Eastern (MID) AF: 0.405 AC: 119 AN: 294

European-Non Finnish (NFE) AF: 0.446 AC: 30289 AN: 67920

Other (OTH) AF: 0.407 AC: 859 AN: 2110

Alfa AF: 0.432 Hom.: 43007

Bravo AF: 0.403

Asia WGS AF: 0.528 AC: 1834 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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.80
CADD	Benign	8.8
DANN	Benign	0.56
PhyloP100		0.19
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1051644; hg19: chr5-126172195; COSMIC: COSV54398965;