5-126777211-G-T

Variant names:

• chr5-126777211-G-T
• rs111865788
• NM_005573.4:c.-298G>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 5 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: Benign. The variant received -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 VariationId 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.

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.-298G>T		5_prime_UTR	Exon 1 of 11	NP_005564.1	P20700
	LMNB1	NM_001198557.2		c.-305G>T		5_prime_UTR	Exon 1 of 11	NP_001185486.1
	LMNB1	NR_134488.1		n.589G>T		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.-298G>T		5_prime_UTR	Exon 1 of 11	ENSP00000261366.5	P20700
	LMNB1	ENST00000395354.1	TSL:1	c.-298G>T		5_prime_UTR	Exon 1 of 6	ENSP00000378761.1	E9PBF6
	LMNB1	ENST00000460265.5	TSL:1	n.-298G>T		non_coding_transcript_exon	Exon 1 of 12	ENSP00000486528.1	A0A0D9SFE5

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

African (AFR) AF: 0.0304 AC: 112 AN: 3682

American (AMR) AF: 0.0563 AC: 199 AN: 3536

Ashkenazi Jewish (ASJ) AF: 0.104 AC: 504 AN: 4842

East Asian (EAS) AF: 0.0320 AC: 367 AN: 11460

South Asian (SAS) AF: 0.0782 AC: 100 AN: 1278

European-Finnish (FIN) AF: 0.0675 AC: 740 AN: 10968

Middle Eastern (MID) AF: 0.0726 AC: 52 AN: 716

European-Non Finnish (NFE) AF: 0.0606 AC: 5044 AN: 83228

Other (OTH) AF: 0.0657 AC: 559 AN: 8502

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

African (AFR) AF: 0.0283 AC: 1177 AN: 41552

American (AMR) AF: 0.0644 AC: 984 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.107 AC: 370 AN: 3470

East Asian (EAS) AF: 0.0274 AC: 141 AN: 5154

South Asian (SAS) AF: 0.0794 AC: 383 AN: 4826

European-Finnish (FIN) AF: 0.0795 AC: 842 AN: 10586

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.0626 AC: 4252 AN: 67966

Other (OTH) AF: 0.0606 AC: 128 AN: 2112

Alfa AF: 0.0551 Hom.: 52

Bravo AF: 0.0526

Asia WGS AF: 0.0470 AC: 163 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Adult-onset autosomal dominant demyelinating leukodystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	14
DANN	Benign	0.92
PhyloP100		0.047
PromoterAI		0.054	Neutral
Mutation Taster		=300/0	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: rs111865788; hg19: chr5-126112903;