Genetic Variant HMGB1:c.-86C>G (chr13-30463766-G-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000399489.5(HMGB1):c.-86C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.234 in 1,003,432 control chromosomes in the GnomAD database, including 30,369 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.20 ( 3676 hom., cov: 33)

Exomes 𝑓: 0.24 ( 26693 hom. )

Consequence

HMGB1
ENST00000399489.5 5_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0490

Publications

72 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.262 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMGB1	NM_002128.7 link	c.-14-72C>G		intron_variant	Intron 1 of 4	ENST00000341423.10	NP_002119.1	P09429A0A024RDR0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HMGB1	ENST00000341423.10 link	c.-14-72C>G		intron_variant	Intron 1 of 4	1	NM_002128.7	ENSP00000345347.5		P09429

Frequencies

GnomAD3 genomes

AF:

0.200

AC:

30412

AN:

152002

Hom.:

3672

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0775

Gnomad AMI

AF:

0.256

Gnomad AMR

AF:

0.170

Gnomad ASJ

AF:

0.181

Gnomad EAS

AF:

0.163

Gnomad SAS

AF:

0.135

Gnomad FIN

AF:

0.359

Gnomad MID

AF:

0.127

Gnomad NFE

AF:

0.266

Gnomad OTH

AF:

0.178

GnomAD4 exome

AF:

0.240

AC:

204445

AN:

851312

Hom.:

26693

Cov.:

AF XY:

0.236

AC XY:

103046

AN XY:

435800

show subpopulations

African (AFR)

AF:

0.0664

AC:

1272

AN:

19162

American (AMR)

AF:

0.168

AC:

4286

AN:

25548

Ashkenazi Jewish (ASJ)

AF:

0.188

AC:

3161

AN:

16828

East Asian (EAS)

AF:

0.135

AC:

4390

AN:

32450

South Asian (SAS)

AF:

0.146

AC:

7699

AN:

52900

European-Finnish (FIN)

AF:

0.348

AC:

10696

AN:

30776

Middle Eastern (MID)

AF:

0.149

AC:

463

AN:

3100

European-Non Finnish (NFE)

AF:

0.259

AC:

163542

AN:

631694

Other (OTH)

AF:

0.230

AC:

8936

AN:

38854

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

7359

14718

22076

29435

36794

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4290

8580

12870

17160

21450

<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:

0.200

AC:

30419

AN:

152120

Hom.:

3676

Cov.:

AF XY:

0.199

AC XY:

14831

AN XY:

74360

show subpopulations

African (AFR)

AF:

0.0773

AC:

3212

AN:

41532

American (AMR)

AF:

0.169

AC:

2585

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.181

AC:

628

AN:

3470

East Asian (EAS)

AF:

0.163

AC:

844

AN:

5182

South Asian (SAS)

AF:

0.135

AC:

652

AN:

4826

European-Finnish (FIN)

AF:

0.359

AC:

3784

AN:

10534

Middle Eastern (MID)

AF:

0.126

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.266

AC:

18058

AN:

67988

Other (OTH)

AF:

0.183

AC:

386

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1206

2412

3617

4823

6029

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

322

644

966

1288

1610

<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:

0.153

Hom.:

374

Bravo

AF:

0.180

Asia WGS

AF:

0.177

AC:

618

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

2.4

(source)

DANN

Benign

0.45

PhyloP100

-0.049

PromoterAI

0.025

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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