13-30461417-A-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP2BP4_StrongBS2

The NM_002128.7(HMGB1):c.588T>G(p.Asp196Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000175 in 1,597,710 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000060 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

HMGB1
NM_002128.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.479

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PP2

Missense variant where missense usually causes diseases, HMGB1

BP4

Computational evidence support a benign effect (MetaRNN=0.031963527).

BS2

High AC in GnomAd at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HMGB1	NM_002128.7 linkuse as main transcript	c.588T>G	p.Asp196Glu	missense_variant	5/5	ENST00000341423.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HMGB1	ENST00000341423.10 linkuse as main transcript	c.588T>G	p.Asp196Glu	missense_variant	5/5	1	NM_002128.7	P1

Frequencies

GnomAD3 genomes

AF:

0.0000599

AC:

AN:

150344

Hom.:

Cov.:

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:

0.0000148

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000198

AC:

AN:

151632

Hom.:

AF XY:

0.0000124

AC XY:

AN XY:

80452

show subpopulations

Gnomad AFR exome

AF:

0.000244

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000167

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000131

AC:

AN:

1447366

Hom.:

Cov.:

AF XY:

0.0000153

AC XY:

AN XY:

719438

show subpopulations

Gnomad4 AFR exome

AF:

0.000214

Gnomad4 AMR exome

AF:

0.0000235

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000118

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000904

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000599

AC:

AN:

150344

Hom.:

Cov.:

AF XY:

0.0000409

AC XY:

AN XY:

73366

show subpopulations

Gnomad4 AFR

AF:

0.000197

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:

0.0000148

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.00000910

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 30, 2024

The c.588T>G (p.D196E) alteration is located in exon 5 (coding exon 4) of the HMGB1 gene. This alteration results from a T to G substitution at nucleotide position 588, causing the aspartic acid (D) at amino acid position 196 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.47

Cadd

Benign

Dann

Benign

0.81

DEOGEN2

Benign

0.10

T;T;T;T

Eigen

Benign

-0.93

Eigen_PC

Benign

-0.73

FATHMM_MKL

Benign

0.50

M_CAP

Benign

0.0090

MetaRNN

Benign

0.032

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.025

N;N;N;N

MutationTaster

Benign

0.99

D;D;D;D;D

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.67

N;N;N;N

REVEL

Benign

0.029

Sift

Benign

0.084

T;T;T;T

Sift4G

Benign

0.86

T;T;T;T

Polyphen

0.0

B;B;B;B

Vest4

0.14

MutPred

0.25

Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);

MVP

0.48

MPC

.;4.45352357014E-4;.;.

ClinPred

0.0052

GERP RS

0.67

RBP_binding_hub_radar

1.0

RBP_regulation_power_radar

3.8

Varity_R

0.028

gMVP

0.020

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

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