Variant 13-30461496-G-A details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_002128.7(HMGB1):c.509C>T(p.Ala170Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000254 in 1,563,354 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00025 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00025 ( 0 hom. )

Consequence

HMGB1
NM_002128.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.48

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:

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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=0.019554347).

BS2

High AC in GnomAd at 38 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HMGB1	NM_002128.7 linkuse as main transcript	c.509C>T	p.Ala170Val	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.509C>T	p.Ala170Val	missense_variant	5/5	1	NM_002128.7	P1

Frequencies

GnomAD3 genomes

AF:

0.000253

AC:

AN:

150206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000492

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000199

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000199

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000458

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000193

AC:

AN:

186634

Hom.:

AF XY:

0.000169

AC XY:

AN XY:

100458

show subpopulations

Gnomad AFR exome

AF:

0.0000901

Gnomad AMR exome

AF:

0.000149

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000164

Gnomad NFE exome

AF:

0.000351

Gnomad OTH exome

AF:

0.000202

GnomAD4 exome

AF:

0.000254

AC:

359

AN:

1413030

Hom.:

Cov.:

AF XY:

0.000237

AC XY:

166

AN XY:

699146

show subpopulations

Gnomad4 AFR exome

AF:

0.0000312

Gnomad4 AMR exome

AF:

0.0000813

Gnomad4 ASJ exome

AF:

0.0000395

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000398

Gnomad4 NFE exome

AF:

0.000292

Gnomad4 OTH exome

AF:

0.000291

GnomAD4 genome

AF:

0.000253

AC:

AN:

150324

Hom.:

Cov.:

AF XY:

0.000150

AC XY:

AN XY:

73242

show subpopulations

Gnomad4 AFR

AF:

0.0000491

Gnomad4 AMR

AF:

0.000198

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000199

Gnomad4 NFE

AF:

0.000458

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000308

Hom.:

Bravo

AF:

0.000291

ESP6500AA

AF:

0.000235

AC:

ESP6500EA

AF:

0.000240

AC:

ExAC

AF:

0.000218

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

Aug 16, 2021

The c.509C>T (p.A170V) alteration is located in exon 5 (coding exon 4) of the HMGB1 gene. This alteration results from a C to T substitution at nucleotide position 509, causing the alanine (A) at amino acid position 170 to be replaced by a valine (V). 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

0.098

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.50

Cadd

Benign

Dann

Uncertain

0.98

DEOGEN2

Benign

0.19

T;T;T;T

Eigen

Benign

-0.19

Eigen_PC

Benign

-0.097

FATHMM_MKL

Benign

0.39

M_CAP

Benign

0.0089

MetaRNN

Benign

0.020

T;T;T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

1.0

N;N;N;N;N;N

PrimateAI

Benign

0.48

PROVEAN

Benign

-1.9

N;N;N;N

REVEL

Benign

0.043

Sift

Benign

0.13

T;T;T;T

Sift4G

Benign

0.24

T;T;T;T

Polyphen

0.0

B;B;B;B

Vest4

0.046

MVP

0.62

MPC

.;4.13900734895E-4;.;.

ClinPred

0.031

GERP RS

3.7

Varity_R

0.056

gMVP

0.11

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