13-30461464-T-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PP2 BP4_Strong BP6_Moderate BS2

The NM_002128.7(HMGB1):c.541A>G(p.Ser181Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00198 in 1,559,298 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0021 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (6 hom.)
• Consequence: HMGB1 NM_002128.7 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.87

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• PP2: Missense variant where missense usually causes diseases, HMGB1
• BP4: Computational evidence support a benign effect (MetaRNN=0.0064373314).
• BP6: Variant 13-30461464-T-C is Benign according to our data. Variant chr13-30461464-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 710363.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 314 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HMGB1	NM_002128.7	c.541A>G	p.Ser181Gly	missense_variant	5/5	ENST00000341423.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HMGB1	ENST00000341423.10	c.541A>G	p.Ser181Gly	missense_variant	5/5	1	NM_002128.7	P1

Frequencies

GnomAD3 genomes AF: 0.00206 AC: 314 AN: 152066 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000435

Gnomad AMI AF: 0.00220

Gnomad AMR AF: 0.00642

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00263

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00189 AC: 308 AN: 162744 Hom.: 0 AF XY: 0.00203 AC XY: 176 AN XY: 86552

Gnomad AFR exome AF: 0.000434

Gnomad AMR exome AF: 0.00306

Gnomad ASJ exome AF: 0.000228

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00263

Gnomad FIN exome AF: 0.000315

Gnomad NFE exome AF: 0.00234

Gnomad OTH exome AF: 0.00240

GnomAD4 exome AF: 0.00197 AC: 2767 AN: 1407114 Hom.: 6 Cov.: 32 AF XY: 0.00205 AC XY: 1424 AN XY: 695628

Gnomad4 AFR exome AF: 0.000314

Gnomad4 AMR exome AF: 0.00252

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000265

Gnomad4 SAS exome AF: 0.00254

Gnomad4 FIN exome AF: 0.000303

Gnomad4 NFE exome AF: 0.00214

Gnomad4 OTH exome AF: 0.00179

GnomAD4 genome AF: 0.00206 AC: 314 AN: 152184 Hom.: 0 Cov.: 32 AF XY: 0.00207 AC XY: 154 AN XY: 74412

Gnomad4 AFR AF: 0.000433

Gnomad4 AMR AF: 0.00641

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00249

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00263

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00183 Hom.: 0

Bravo AF: 0.00205

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000606 AC: 5

ExAC AF: 0.00119 AC: 137

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.21
Cadd	Uncertain	24
Dann	Uncertain	0.98
DEOGEN2	Benign	0.19	T;T;T;T
Eigen	Benign	-0.0067
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.82	D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.0064	T;T;T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Uncertain	2.4	M;M;M;M
MutationTaster	Benign	1.0	D;N;N;N;N
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.9	N;N;N;N
REVEL	Benign	0.12
Sift	Uncertain	0.0080	D;D;D;D
Sift4G	Benign	0.11	T;T;T;T
Polyphen		0.015	B;B;B;B
Vest4		0.29
MVP		0.51
MPC		.;4.45352357014E-4;.;.
ClinPred		0.023	T
GERP RS		5.7
Varity_R		0.18
gMVP		0.047

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

Other links and lift over

dbSNP: rs201813276; hg19: chr13-31035601;