rs190839668

Variant names:

• chr13-30461496-G-A
• rs190839668
• NM_002128.7:c.509C>T

Your query was ambiguous. Multiple possible variants found:

• chr13-30461496-G-A
• chr13-30461496-G-C

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

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. 15/21 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.48
• 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.019554347).
• BS2: High AC in GnomAd4 at 38 AD gene.

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.509C>T	p.Ala170Val	missense	Exon 5 of 5	NP_002119.1	P09429
	HMGB1	NM_001313892.2		c.509C>T	p.Ala170Val	missense	Exon 5 of 5	NP_001300821.1	P09429
	HMGB1	NM_001313893.1		c.509C>T	p.Ala170Val	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.509C>T	p.Ala170Val	missense	Exon 5 of 5	ENSP00000345347.5	P09429
	HMGB1	ENST00000399489.5	TSL:1	c.*82C>T		3_prime_UTR	Exon 5 of 5	ENSP00000382412.1	Q5T7C4
	HMGB1	ENST00000927783.1		c.518C>T	p.Ala173Val	missense	Exon 5 of 5	ENSP00000597842.1

Frequencies

GnomAD3 genomes AF: 0.000253 AC: 38 AN: 150206 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.000193 AC: 36 AN: 186634 AF XY: 0.000169

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 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.: 0 Cov.: 32 AF XY: 0.000237 AC XY: 166 AN XY: 699146

African (AFR) AF: 0.0000312 AC: 1 AN: 32088

American (AMR) AF: 0.0000813 AC: 3 AN: 36918

Ashkenazi Jewish (ASJ) AF: 0.0000395 AC: 1 AN: 25312

East Asian (EAS) AF: 0.00 AC: 0 AN: 38344

South Asian (SAS) AF: 0.00 AC: 0 AN: 81042

European-Finnish (FIN) AF: 0.000398 AC: 20 AN: 50280

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5006

European-Non Finnish (NFE) AF: 0.000292 AC: 317 AN: 1085696

Other (OTH) AF: 0.000291 AC: 17 AN: 58344

GnomAD4 genome AF: 0.000253 AC: 38 AN: 150324 Hom.: 0 Cov.: 32 AF XY: 0.000150 AC XY: 11 AN XY: 73242

African (AFR) AF: 0.0000491 AC: 2 AN: 40774

American (AMR) AF: 0.000198 AC: 3 AN: 15126

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5122

South Asian (SAS) AF: 0.00 AC: 0 AN: 4788

European-Finnish (FIN) AF: 0.000199 AC: 2 AN: 10036

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000458 AC: 31 AN: 67726

Other (OTH) AF: 0.00 AC: 0 AN: 2082

Alfa AF: 0.000308 Hom.: 0

Bravo AF: 0.000291

ESP6500AA AF: 0.000235 AC: 1

ESP6500EA AF: 0.000240 AC: 2

ExAC AF: 0.000218 AC: 26

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.097
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.0089	T
MetaRNN	Benign	0.020	T
MetaSVM	Benign	-1.0	T
PhyloP100		2.5
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.043
Sift	Benign	0.13	T
Sift4G	Benign	0.24	T
Polyphen		0.0	B
Vest4		0.046
MVP		0.62
MPC		0.00041
ClinPred		0.031	T
GERP RS		3.7
Varity_R		0.056
gMVP		0.11
Mutation Taster		=90/10	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: rs190839668; hg19: chr13-31035633;