13-30463766-G-C

Variant names:

• chr13-30463766-G-C
• rs2249825
• ENST00000399489.5:c.-86C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0490
• Publications: 72 publications found

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

ENSG00000285840 (HGNC:):

ACMG classification

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000399489.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMGB1	NM_002128.7	MANE Select	c.-14-72C>G		intron	N/A	NP_002119.1
	HMGB1	NM_001313892.2		c.-14-72C>G		intron	N/A	NP_001300821.1
	HMGB1	NM_001313893.1		c.-14-72C>G		intron	N/A	NP_001300822.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMGB1	ENST00000399489.5	TSL:1	c.-86C>G		5_prime_UTR	Exon 1 of 5	ENSP00000382412.1
	HMGB1	ENST00000341423.10	TSL:1 MANE Select	c.-14-72C>G		intron	N/A	ENSP00000345347.5
	HMGB1	ENST00000468384.1	TSL:1	n.120-72C>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.200 AC: 30412 AN: 152002 Hom.: 3672 Cov.: 33

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.: 11 AF XY: 0.236 AC XY: 103046 AN XY: 435800

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

GnomAD4 genome AF: 0.200 AC: 30419 AN: 152120 Hom.: 3676 Cov.: 33 AF XY: 0.199 AC XY: 14831 AN XY: 74360

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: 37 AN: 294

European-Non Finnish (NFE) AF: 0.266 AC: 18058 AN: 67988

Other (OTH) AF: 0.183 AC: 386 AN: 2108

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.4
DANN	Benign	0.45
PhyloP100		-0.049
PromoterAI		0.025	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2249825; hg19: chr13-31037903;