5-126836503-C-T

Variant names:

• chr5-126836503-C-T
• rs1051644
• NM_005573.4:c.*239C>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.*239C>T variant causes a 3 prime UTR 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 NM_005573.4 3_prime_UTR
• 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: 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=-0.8).
• 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.

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.*239C>T		3_prime_UTR	Exon 11 of 11	NP_005564.1	P20700
	LMNB1	NM_001198557.2		c.*239C>T		3_prime_UTR	Exon 11 of 11	NP_001185486.1
	LMNB1	NR_134488.1		n.2964C>T		non_coding_transcript_exon	Exon 12 of 12

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LMNB1	ENST00000261366.10	TSL:1 MANE Select	c.*239C>T		3_prime_UTR	Exon 11 of 11	ENSP00000261366.5	P20700
	LMNB1	ENST00000460265.5	TSL:1	n.*1088C>T		non_coding_transcript_exon	Exon 12 of 12	ENSP00000486528.1	A0A0D9SFE5
	LMNB1	ENST00000460265.5	TSL:1	n.*1088C>T		3_prime_UTR	Exon 12 of 12	ENSP00000486528.1	A0A0D9SFE5

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

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	-0.80
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;