rs116519295

Variant names:

• chr5-126776477-T-C
• rs116519295
• ENST00000509185.2:n.10A>G

Variant summary

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

The NR_134485.1(LMNB1-DT):​n.10A>G 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 0.0313 in 152,260 control chromosomes in the GnomAD database, including 104 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.031 (104 hom., cov: 33)
  • Exomes 𝑓: 0.25 (0 hom.)
• Consequence: LMNB1-DT NR_134485.1 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.11
• Publications: 0 publications found

Genes affected

LMNB1-DT (HGNC:53089): (LMNB1 divergent transcript)

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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• 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=-0.82).
• BP6: Variant 5-126776477-T-C is Benign according to our data. Variant chr5-126776477-T-C is described in ClinVar as Benign. ClinVar VariationId is 1235155.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0518 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NR_134485.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LMNB1-DT	NR_134485.1		n.10A>G		non_coding_transcript_exon	Exon 1 of 4
	LMNB1	NR_134488.1		n.-146T>C		upstream_gene	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LMNB1-DT	ENST00000509185.2	TSL:5	n.10A>G		non_coding_transcript_exon	Exon 1 of 4
	LMNB1-DT	ENST00000815038.1		n.70A>G		non_coding_transcript_exon	Exon 1 of 2
	LMNB1-DT	ENST00000815039.1		n.47A>G		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes AF: 0.0314 AC: 4770 AN: 152138 Hom.: 104 Cov.: 33

Gnomad AFR AF: 0.0538

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0353

Gnomad ASJ AF: 0.0311

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.00455

Gnomad FIN AF: 0.0332

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.0205

Gnomad OTH AF: 0.0406

GnomAD4 exome AF: 0.250 AC: 1 AN: 4 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 2

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.500 AC: 1 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 2

Other (OTH) AC: 0 AN: 0

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0313 AC: 4766 AN: 152256 Hom.: 104 Cov.: 33 AF XY: 0.0307 AC XY: 2282 AN XY: 74450

African (AFR) AF: 0.0537 AC: 2229 AN: 41542

American (AMR) AF: 0.0352 AC: 539 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0311 AC: 108 AN: 3470

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5182

South Asian (SAS) AF: 0.00435 AC: 21 AN: 4826

European-Finnish (FIN) AF: 0.0332 AC: 352 AN: 10606

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.0205 AC: 1395 AN: 68016

Other (OTH) AF: 0.0407 AC: 86 AN: 2114

Alfa AF: 0.0188 Hom.: 39

Bravo AF: 0.0325

Asia WGS AF: 0.00779 AC: 28 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.79
DANN	Benign	0.48
PhyloP100		-2.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs116519295; hg19: chr5-126112169;