5-126777350-C-T

Variant names:

• chr5-126777350-C-T
• rs886059857
• NM_005573.4:c.-159C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005573.4(LMNB1):​c.-159C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000153 in 652,644 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: LMNB1 NM_005573.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.305
• Publications: 0 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: 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005573.4. 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	NM_005573.4	MANE Select	c.-159C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 11	NP_005564.1	P20700
	LMNB1	NM_005573.4	MANE Select	c.-159C>T		5_prime_UTR	Exon 1 of 11	NP_005564.1	P20700
	LMNB1	NM_001198557.2		c.-272+106C>T		intron	N/A	NP_001185486.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LMNB1	ENST00000261366.10	TSL:1 MANE Select	c.-159C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 11	ENSP00000261366.5	P20700
	LMNB1	ENST00000395354.1	TSL:1	c.-159C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 6	ENSP00000378761.1	E9PBF6
	LMNB1	ENST00000261366.10	TSL:1 MANE Select	c.-159C>T		5_prime_UTR	Exon 1 of 11	ENSP00000261366.5	P20700

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000153 AC: 1 AN: 652644 Hom.: 0 Cov.: 9 AF XY: 0.00 AC XY: 0 AN XY: 315828

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

African (AFR) AF: 0.00 AC: 0 AN: 13988

American (AMR) AF: 0.00 AC: 0 AN: 7140

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10858

East Asian (EAS) AF: 0.00 AC: 0 AN: 22474

South Asian (SAS) AF: 0.00 AC: 0 AN: 13048

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 21568

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2080

European-Non Finnish (NFE) AF: 0.00000188 AC: 1 AN: 532420

Other (OTH) AF: 0.00 AC: 0 AN: 29068

⚠️ 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 Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	15
DANN	Benign	0.95
PhyloP100		0.30
PromoterAI		-0.061	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs886059857; hg19: chr5-126113042;