chr13-30461464-T-C

Variant names:

• chr13-30461464-T-C
• rs201813276
• NM_002128.7:c.541A>G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong 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. 13/22 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.87
• Publications: 2 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 -16 ACMG points.

• 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 VariationId is 710363.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 314 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.541A>G	p.Ser181Gly	missense	Exon 5 of 5	NP_002119.1	P09429
	HMGB1	NM_001313892.2		c.541A>G	p.Ser181Gly	missense	Exon 5 of 5	NP_001300821.1	P09429
	HMGB1	NM_001313893.1		c.541A>G	p.Ser181Gly	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.541A>G	p.Ser181Gly	missense	Exon 5 of 5	ENSP00000345347.5	P09429
	HMGB1	ENST00000399489.5	TSL:1	c.*114A>G		3_prime_UTR	Exon 5 of 5	ENSP00000382412.1	Q5T7C4
	HMGB1	ENST00000927783.1		c.550A>G	p.Ser184Gly	missense	Exon 5 of 5	ENSP00000597842.1

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

GnomAD2 exomes AF: 0.00189 AC: 308 AN: 162744 AF XY: 0.00203

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 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

African (AFR) AF: 0.000314 AC: 10 AN: 31878

American (AMR) AF: 0.00252 AC: 92 AN: 36532

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25336

East Asian (EAS) AF: 0.0000265 AC: 1 AN: 37706

South Asian (SAS) AF: 0.00254 AC: 204 AN: 80352

European-Finnish (FIN) AF: 0.000303 AC: 15 AN: 49448

Middle Eastern (MID) AF: 0.00515 AC: 23 AN: 4466

European-Non Finnish (NFE) AF: 0.00214 AC: 2318 AN: 1083266

Other (OTH) AF: 0.00179 AC: 104 AN: 58130

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

African (AFR) AF: 0.000433 AC: 18 AN: 41524

American (AMR) AF: 0.00641 AC: 98 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00249 AC: 12 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

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

European-Non Finnish (NFE) AF: 0.00263 AC: 179 AN: 67988

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

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

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.0067
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.0064	T
MetaSVM	Benign	-0.81	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		2.9
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.12
Sift	Uncertain	0.0080	D
Sift4G	Benign	0.11	T
Polyphen		0.015	B
Vest4		0.29
MVP		0.51
MPC		0.00045
ClinPred		0.023	T
GERP RS		5.7
Varity_R		0.18
gMVP		0.047
Mutation Taster		=60/40	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: rs201813276; hg19: chr13-31035601;