Variant X-150987884-A-AGAG details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_005342.4(HMGB3):c.594_596dupGGA(p.Glu198dup) variant causes a disruptive inframe insertion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000137 in 1,177,078 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 39 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., 4 hem., cov: 23)

Exomes 𝑓: 0.00014 ( 0 hom. 35 hem. )

Consequence

HMGB3
NM_005342.4 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.34

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High Hemizygotes in GnomAd4 at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HMGB3	NM_005342.4 linkuse as main transcript	c.594_596dupGGA	p.Glu198dup	disruptive_inframe_insertion	5/5	ENST00000325307.12	NP_005333.2	O15347

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
HMGB3	ENST00000325307.12 linkuse as main transcript	c.594_596dupGGA	p.Glu198dup	disruptive_inframe_insertion	5/5	1	NM_005342.4	ENSP00000359393.3	O15347
HMGB3	ENST00000448905.6 linkuse as main transcript	c.594_596dupGGA	p.Glu198dup	disruptive_inframe_insertion	5/5	1		ENSP00000442758.1	O15347
HMGB3	ENST00000419110.5 linkuse as main transcript	c.7_8insGAG		downstream_gene_variant		3		ENSP00000410354.1	E7ES08

Frequencies

GnomAD3 genomes

AF:

0.000126

AC:

AN:

111043

Hom.:

Cov.:

AF XY:

0.000120

AC XY:

AN XY:

33297

show subpopulations

Gnomad AFR

AF:

0.000197

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.000668

GnomAD3 exomes

AF:

0.000189

AC:

AN:

169187

Hom.:

AF XY:

0.000115

AC XY:

AN XY:

60757

show subpopulations

Gnomad AFR exome

AF:

0.000245

Gnomad AMR exome

AF:

0.000345

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000759

Gnomad SAS exome

AF:

0.000332

Gnomad FIN exome

AF:

0.000102

Gnomad NFE exome

AF:

0.000153

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000138

AC:

147

AN:

1065989

Hom.:

Cov.:

AF XY:

0.000102

AC XY:

AN XY:

344715

show subpopulations

Gnomad4 AFR exome

AF:

0.000193

Gnomad4 AMR exome

AF:

0.000258

Gnomad4 ASJ exome

AF:

0.0000524

Gnomad4 EAS exome

AF:

0.000167

Gnomad4 SAS exome

AF:

0.000473

Gnomad4 FIN exome

AF:

0.0000309

Gnomad4 NFE exome

AF:

0.000116

Gnomad4 OTH exome

AF:

0.000133

GnomAD4 genome

AF:

0.000126

AC:

AN:

111089

Hom.:

Cov.:

AF XY:

0.000120

AC XY:

AN XY:

33353

show subpopulations

Gnomad4 AFR

AF:

0.000196

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.000660

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 16, 2023

This variant, c.594_596dup, results in the insertion of 1 amino acid(s) of the HMGB3 protein (p.Glu198dup), but otherwise preserves the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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. This variant has not been reported in the literature in individuals affected with HMGB3-related conditions. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over