5-126777509-A-G

Variant names:

• chr5-126777509-A-G
• rs2112911599
• NM_005573.4:c.1A>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PVS1_Supporting 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
• 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 3 ACMG points.

• PVS1: Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 11 codons. Genomic position: 126777539. Lost 0.018 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage

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.1A>G	p.Met1?	start_lost	Exon 1 of 11	NP_005564.1	P20700
	LMNB1	NM_001198557.2		c.-272+265A>G		intron	N/A	NP_001185486.1
	LMNB1	NR_134488.1		n.887A>G		non_coding_transcript_exon	Exon 1 of 12

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LMNB1	ENST00000261366.10	TSL:1 MANE Select	c.1A>G	p.Met1?	start_lost	Exon 1 of 11	ENSP00000261366.5	P20700
	LMNB1	ENST00000395354.1	TSL:1	c.1A>G	p.Met1?	start_lost	Exon 1 of 6	ENSP00000378761.1	E9PBF6
	LMNB1	ENST00000460265.5	TSL:1	n.1A>G		non_coding_transcript_exon	Exon 1 of 12	ENSP00000486528.1	A0A0D9SFE5

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

⚠️ 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: 23524

American (AMR) AF: 0.00 AC: 0 AN: 9574

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15972

East Asian (EAS) AF: 0.00 AC: 0 AN: 27180

South Asian (SAS) AF: 0.00 AC: 0 AN: 42894

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38814

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3368

European-Non Finnish (NFE) AF: 0.00000102 AC: 1 AN: 982344

Other (OTH) AF: 0.00 AC: 0 AN: 48402

⚠️ 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

ClinVar

ClinVar submissions

Significance: Uncertain significance

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_addAF	Uncertain	0.086	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	22
DANN	Benign	0.60
DEOGEN2	Uncertain	0.58	D
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.57
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Benign	-0.53	T
PhyloP100		5.2
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.38
Sift	Benign	0.031	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.0050	B
Vest4		0.83
MutPred		0.96		Loss of MoRF binding (P = 0.1176)
MVP		0.85
ClinPred		0.97	D
GERP RS		1.5
PromoterAI		-0.44	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Varity_R		0.65
gMVP		0.24
Mutation Taster		=78/122	disease causing

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: rs2112911599; hg19: chr5-126113201;