rs4540927

Variant names:

• chr13-30462407-G-A
• rs4540927
• NM_002128.7:c.471+131C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_002128.7(HMGB1):​c.471+131C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00205 in 808,764 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0072 (13 hom., cov: 32)
  • Exomes 𝑓: 0.00085 (5 hom.)
• Consequence: HMGB1 NM_002128.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0240
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00724 (1102/152268) while in subpopulation AFR AF = 0.0257 (1067/41532). AF 95% confidence interval is 0.0244. There are 13 homozygotes in GnomAd4. There are 520 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1102 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.471+131C>T		intron	N/A	NP_002119.1	P09429
	HMGB1	NM_001313892.2		c.471+131C>T		intron	N/A	NP_001300821.1	P09429
	HMGB1	NM_001313893.1		c.471+131C>T		intron	N/A	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.471+131C>T		intron	N/A	ENSP00000345347.5	P09429
	HMGB1	ENST00000399489.5	TSL:1	c.471+131C>T		intron	N/A	ENSP00000382412.1	Q5T7C4
	HMGB1	ENST00000927783.1		c.480+122C>T		intron	N/A	ENSP00000597842.1

Frequencies

GnomAD3 genomes AF: 0.00722 AC: 1098 AN: 152150 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.0257

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00335

GnomAD4 exome AF: 0.000848 AC: 557 AN: 656496 Hom.: 5 Cov.: 8 AF XY: 0.000654 AC XY: 233 AN XY: 356034

African (AFR) AF: 0.0244 AC: 446 AN: 18316

American (AMR) AF: 0.000780 AC: 34 AN: 43566

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21114

East Asian (EAS) AF: 0.00 AC: 0 AN: 36090

South Asian (SAS) AF: 0.0000431 AC: 3 AN: 69630

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45020

Middle Eastern (MID) AF: 0.000709 AC: 3 AN: 4232

European-Non Finnish (NFE) AF: 0.0000312 AC: 12 AN: 384336

Other (OTH) AF: 0.00173 AC: 59 AN: 34192

GnomAD4 genome AF: 0.00724 AC: 1102 AN: 152268 Hom.: 13 Cov.: 32 AF XY: 0.00698 AC XY: 520 AN XY: 74456

African (AFR) AF: 0.0257 AC: 1067 AN: 41532

American (AMR) AF: 0.00150 AC: 23 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68030

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00628 Hom.: 0

Bravo AF: 0.00776

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.3
DANN	Benign	0.19
PhyloP100		0.024
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	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: rs4540927; hg19: chr13-31036544;