Genetic Variant HMGB3:p.Lys161IlefsTer55 (chrX-150987788-C-CTA) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_005342.4(HMGB3):c.480_481dupTA(p.Lys161IlefsTer55) variant causes a frameshift change. The variant allele was found at a frequency of 0.000000915 in 1,092,385 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 9.2e-7 ( 0 hom. 0 hem. )

Consequence

HMGB3
NM_005342.4 frameshift

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:1O:1

Conservation

PhyloP100: 6.16

Publications

3 publications found

Variant links:

Genes affected

HMGB3 (HGNC:5004): (high mobility group box 3) This gene encodes a member of a family of proteins containing one or more high mobility group DNA-binding motifs. The encoded protein plays an important role in maintaining stem cell populations, and may be aberrantly expressed in tumor cells. A mutation in this gene was associated with microphthalmia, syndromic 13. There are numerous pseudogenes of this gene on multiple chromosomes. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

HMGB3 Gene-Disease associations (from GenCC):

X-linked colobomatous microphthalmia-microcephaly-intellectual disability-short stature syndrome
Inheritance: XL, Unknown Classification: LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)

HMGB3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005342.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
HMGB3	NM_005342.4	MANE Select	c.480_481dupTA	p.Lys161IlefsTer55	frameshift	Exon 5 of 5	NP_005333.2
HMGB3	NM_001440773.1		c.546_547dupTA	p.Lys183IlefsTer55	frameshift	Exon 5 of 5	NP_001427702.1
HMGB3	NM_001301231.2		c.540_541dupTA	p.Lys181IlefsTer55	frameshift	Exon 5 of 5	NP_001288160.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
HMGB3	ENST00000325307.12	TSL:1 MANE Select	c.480_481dupTA	p.Lys161IlefsTer55	frameshift	Exon 5 of 5	ENSP00000359393.3
HMGB3	ENST00000448905.6	TSL:1	c.480_481dupTA	p.Lys161IlefsTer47	frameshift	Exon 5 of 5	ENSP00000442758.1
HMGB3	ENST00000455596.5	TSL:1	c.480_481dupTA	p.Lys161IlefsTer34	frameshift	Exon 5 of 5	ENSP00000405601.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.15e-7

AC:

AN:

1092385

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

358959

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26279

American (AMR)

AF:

0.00

AC:

AN:

34912

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19259

East Asian (EAS)

AF:

0.00

AC:

AN:

30176

South Asian (SAS)

AF:

0.00

AC:

AN:

53361

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40027

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3040

European-Non Finnish (NFE)

AF:

0.00000119

AC:

AN:

839537

Other (OTH)

AF:

0.00

AC:

AN:

45794

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:1Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1Other:1

Jun 24, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This frameshift has been observed in individual(s) with X-linked colobomatous microphthalmia syndrome. (PMID: 24993872). This variant is not present in population databases (gnomAD no frequency). This sequence change results in a frameshift in the HMGB3 gene (p.Lys161Ilefs*55). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 40 amino acid(s) of the HMGB3 protein and extend the protein by 14 additional amino acid residues.

Johns Hopkins Genetic Resources Core Facility; Johns Hopkins University

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

X-linked colobomatous microphthalmia-microcephaly-intellectual disability-short stature syndrome

Pathogenic:1

Jul 03, 2014

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

6.2

Mutation Taster

=9/191

disease causing (ClinVar)

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over