Genetic Variant HMGB1:c.-326_-325dupTT (chr13-30464004-T-TAA) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1BS2

The ENST00000399489.5(HMGB1):c.-326_-325dupTT variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00322 in 664,568 control chromosomes in the GnomAD database, including 13 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0033 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0032 ( 10 hom. )

Consequence

HMGB1
ENST00000399489.5 5_prime_UTR

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.740

Publications

2 publications found

Variant links:

Genes affected

HMGB1 (HGNC:4983): (high mobility group box 1) This gene encodes a protein that belongs to the High Mobility Group-box superfamily. The encoded non-histone, nuclear DNA-binding protein regulates transcription, and is involved in organization of DNA. This protein plays a role in several cellular processes, including inflammation, cell differentiation and tumor cell migration. Multiple pseudogenes of this gene have been identified. Alternative splicing results in multiple transcript variants that encode the same protein. [provided by RefSeq, Sep 2015]

HMGB1 Gene-Disease associations (from GenCC):

intellectual disability
Inheritance: AD Classification: LIMITED Submitted by: G2P

HMGB1 links:

ENSG00000285840 (HGNC:):

ENSG00000285840 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0032 (1638/512336) while in subpopulation MID AF = 0.0249 (27/1084). AF 95% confidence interval is 0.0176. There are 10 homozygotes in GnomAdExome4. There are 783 alleles in the male GnomAdExome4 subpopulation. Median coverage is 8. This position passed quality control check.

BS2

High AC in GnomAd4 at 499 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMGB1	NM_002128.7 link	c.-14-312_-14-311dupTT		intron_variant	Intron 1 of 4	ENST00000341423.10	NP_002119.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HMGB1	ENST00000341423.10 link	c.-14-312_-14-311dupTT		intron_variant	Intron 1 of 4	1	NM_002128.7	ENSP00000345347.5

Frequencies

GnomAD3 genomes

AF:

0.00328

AC:

499

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000579

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.00615

Gnomad ASJ

AF:

0.00490

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0145

Gnomad FIN

AF:

0.00132

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.00385

Gnomad OTH

AF:

0.00288

GnomAD4 exome

AF:

0.00320

AC:

1638

AN:

512336

Hom.:

Cov.:

AF XY:

0.00322

AC XY:

783

AN XY:

242802

show subpopulations

African (AFR)

AF:

0.000106

AC:

AN:

9424

American (AMR)

AF:

0.00531

AC:

AN:

1694

Ashkenazi Jewish (ASJ)

AF:

0.00307

AC:

AN:

3910

East Asian (EAS)

AF:

0.00

AC:

AN:

3390

South Asian (SAS)

AF:

0.0142

AC:

162

AN:

11390

European-Finnish (FIN)

AF:

0.00112

AC:

AN:

892

Middle Eastern (MID)

AF:

0.0249

AC:

AN:

1084

European-Non Finnish (NFE)

AF:

0.00294

AC:

1360

AN:

463088

Other (OTH)

AF:

0.00378

AC:

AN:

17464

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

Heterozygous variant carriers

159

239

318

398

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

152

228

304

380

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00328

AC:

499

AN:

152232

Hom.:

Cov.:

AF XY:

0.00372

AC XY:

277

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.000578

AC:

AN:

41538

American (AMR)

AF:

0.00614

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00490

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.0145

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00132

AC:

AN:

10596

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00385

AC:

262

AN:

68004

Other (OTH)

AF:

0.00285

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

104

130

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00109

Hom.:

Bravo

AF:

0.00324

Asia WGS

AF:

0.00433

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.74

Mutation Taster

=300/0

polymorphism

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over