Genetic Variant HMGB1:p.Ala170Gly (chr13-30461496-G-C) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 2P and 8B. PM2BP4_StrongBS2

The NM_002128.7(HMGB1):c.509C>G(p.Ala170Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000354 in 1,413,030 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A170V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000035 ( 0 hom. )

Consequence

HMGB1
NM_002128.7 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.48

Publications

1 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.058672577).

BS2

High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMGB1	NM_002128.7 link	c.509C>G	p.Ala170Gly	missense_variant	Exon 5 of 5	ENST00000341423.10	NP_002119.1	P09429A0A024RDR0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HMGB1	ENST00000341423.10 link	c.509C>G	p.Ala170Gly	missense_variant	Exon 5 of 5	1	NM_002128.7	ENSP00000345347.5		P09429

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000536

AC:

AN:

186634

AF XY:

0.00000995

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000130

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000354

AC:

AN:

1413030

Hom.:

Cov.:

AF XY:

0.00000572

AC XY:

AN XY:

699146

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32088

American (AMR)

AF:

0.00

AC:

AN:

36918

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25312

East Asian (EAS)

AF:

0.00

AC:

AN:

38344

South Asian (SAS)

AF:

0.00

AC:

AN:

81042

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50280

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5006

European-Non Finnish (NFE)

AF:

0.00000461

AC:

AN:

1085696

Other (OTH)

AF:

0.00

AC:

AN:

58344

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000838

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.11

T;T;T;T

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.16

FATHMM_MKL

Benign

0.32

LIST_S2

Benign

0.84

.;.;.;T

M_CAP

Benign

0.0076

MetaRNN

Benign

0.059

T;T;T;T

MetaSVM

Benign

-1.0

PhyloP100

2.5

PrimateAI

Benign

0.44

PROVEAN

Benign

-0.74

N;N;N;N

REVEL

Benign

0.034

Sift

Benign

0.26

T;T;T;T

Sift4G

Benign

0.28

T;T;T;T

Polyphen

0.0

B;B;B;B

Vest4

0.067

MutPred

0.26

Gain of relative solvent accessibility (P = 0.0023);Gain of relative solvent accessibility (P = 0.0023);Gain of relative solvent accessibility (P = 0.0023);Gain of relative solvent accessibility (P = 0.0023);

MVP

0.57

MPC

.;4.08659019313E-4;.;.

ClinPred

0.14

GERP RS

3.7

Varity_R

0.046

gMVP

0.079

Mutation Taster

=92/8

polymorphism

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over