rs431825172

Variant names:

• chrX-150987788-C-CTA
• rs431825172
• NM_005342.4:c.480_481dupTA

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
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1 O:1
• Conservation: PhyloP100: 6.16
• Publications: 3 publications found

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: Unknown, XL Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P

ACMG classification

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMGB3	NM_005342.4	MANE Select	c.480_481dupTA	p.Lys161IlefsTer55	frameshift	Exon 5 of 5	NP_005333.2	O15347
	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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMGB3	ENST00000325307.12	TSL:1 MANE Select	c.480_481dupTA	p.Lys161IlefsTer55	frameshift	Exon 5 of 5	ENSP00000359393.3	O15347
	HMGB3	ENST00000448905.6	TSL:1	c.480_481dupTA	p.Lys161IlefsTer47	frameshift	Exon 5 of 5	ENSP00000442758.1	O15347
	HMGB3	ENST00000455596.5	TSL:1	c.480_481dupTA	p.Lys161IlefsTer34	frameshift	Exon 5 of 5	ENSP00000405601.1	E7EQU1

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

African (AFR) AF: 0.00 AC: 0 AN: 26279

American (AMR) AF: 0.00 AC: 0 AN: 34912

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19259

East Asian (EAS) AF: 0.00 AC: 0 AN: 30176

South Asian (SAS) AF: 0.00 AC: 0 AN: 53361

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40027

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3040

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 839537

Other (OTH) AF: 0.00 AC: 0 AN: 45794

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (2)
1	-	-	X-linked colobomatous microphthalmia-microcephaly-intellectual disability-short stature syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.2
Mutation Taster		=9/191	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs431825172; hg19: chrX-150156261;