rs431825172

Positions:

• chrX-150987788-C-CTA

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The ENST00000325307.12(HMGB3):​c.480_481dup​(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 ENST00000325307.12 frameshift
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1 O:1
• Conservation: PhyloP100: 6.16

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.209 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HMGB3	NM_005342.4	c.480_481dup	p.Lys161IlefsTer55	frameshift_variant	5/5	ENST00000325307.12	NP_005333.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HMGB3	ENST00000325307.12	c.480_481dup	p.Lys161IlefsTer55	frameshift_variant	5/5	1	NM_005342.4	ENSP00000359393	P1
HMGB3	ENST00000448905.6	c.480_481dup	p.Lys161IlefsTer?	frameshift_variant	5/5	1		ENSP00000442758	P1
HMGB3	ENST00000455596.5	c.480_481dup	p.Lys161IlefsTer?	frameshift_variant	5/5	1		ENSP00000405601
HMGB3	ENST00000419110.5	c.480_481dup	p.Lys161IlefsTer?	frameshift_variant	5/5	3		ENSP00000410354

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.15e-7 AC: 1 AN: 1092385 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 358959

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

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

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1 Other:1

not provided, no classification provided	literature only	Johns Hopkins Genetic Resources Core Facility; Johns Hopkins University	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 24, 2023	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. -

X-linked colobomatous microphthalmia-microcephaly-intellectual disability-short stature syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 03, 2014

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs431825172; hg19: chrX-150156261;