rs10444632

Variant names:

• chr13-30461426-A-C
• rs10444632
• NM_002128.7:c.579T>G

Your query was ambiguous. Multiple possible variants found:

• chr13-30461426-A-C
• chr13-30461426-A-G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002128.7(HMGB1):​c.579T>G​(p.Asp193Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D193D) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HMGB1 NM_002128.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.171
• Publications: 1 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.055137277).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002128.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMGB1	NM_002128.7	MANE Select	c.579T>G	p.Asp193Glu	missense	Exon 5 of 5	NP_002119.1	P09429
	HMGB1	NM_001313892.2		c.579T>G	p.Asp193Glu	missense	Exon 5 of 5	NP_001300821.1	P09429
	HMGB1	NM_001313893.1		c.579T>G	p.Asp193Glu	missense	Exon 5 of 5	NP_001300822.1	P09429

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMGB1	ENST00000341423.10	TSL:1 MANE Select	c.579T>G	p.Asp193Glu	missense	Exon 5 of 5	ENSP00000345347.5	P09429
	HMGB1	ENST00000399489.5	TSL:1	c.*152T>G		3_prime_UTR	Exon 5 of 5	ENSP00000382412.1	Q5T7C4
	HMGB1	ENST00000927783.1		c.588T>G	p.Asp196Glu	missense	Exon 5 of 5	ENSP00000597842.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000139 AC: 2 AN: 1439520 Hom.: 0 Cov.: 32 AF XY: 0.00000280 AC XY: 2 AN XY: 715104

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32548

American (AMR) AF: 0.00 AC: 0 AN: 42002

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25678

East Asian (EAS) AF: 0.00 AC: 0 AN: 39400

South Asian (SAS) AF: 0.00 AC: 0 AN: 84106

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51634

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4224

European-Non Finnish (NFE) AF: 0.00000182 AC: 2 AN: 1100638

Other (OTH) AF: 0.00 AC: 0 AN: 59290

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	13
DANN	Benign	0.48
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.0043	T
MetaRNN	Benign	0.055	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.090	N
PhyloP100		-0.17
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.027
Sift	Uncertain	0.017	D
Sift4G	Benign	0.56	T
Polyphen		0.0	B
Vest4		0.16
MutPred		0.24		Gain of helix (P = 0.0696)
MVP		0.25
MPC		0.00045
ClinPred		0.065	T
GERP RS		-5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.084
gMVP		0.030
Mutation Taster		=91/9	polymorphism

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: rs10444632; hg19: chr13-31035563;