chr13-30466048-G-C

Variant names:

• chr13-30466048-G-C
• rs41477046
• NM_001313893.1:c.-14-2354C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001313893.1(HMGB1):​c.-14-2354C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000197 in 506,914 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 33)
  • Exomes 𝑓: 0.0000020 (0 hom.)
• Consequence: HMGB1 NM_001313893.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.62
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.3).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001313893.1. 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_001313893.1		c.-14-2354C>G		intron	N/A	NP_001300822.1
	HMGB1	NM_001370340.1		c.-14-2354C>G		intron	N/A	NP_001357269.1
	HMGB1	NM_002128.7	MANE Select	c.-267C>G		upstream_gene	N/A	NP_002119.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMGB1	ENST00000405805.5	TSL:2	c.-14-2354C>G		intron	N/A	ENSP00000384678.1
	HMGB1	ENST00000897840.1		c.-14-2354C>G		intron	N/A	ENSP00000567899.1
	HMGB1	ENST00000897841.1		c.-14-2354C>G		intron	N/A	ENSP00000567900.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000197 AC: 1 AN: 506914 Hom.: 0 AF XY: 0.00000421 AC XY: 1 AN XY: 237360

⚠️ 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: 9490

American (AMR) AF: 0.00 AC: 0 AN: 592

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3150

East Asian (EAS) AF: 0.00 AC: 0 AN: 2148

South Asian (SAS) AF: 0.00 AC: 0 AN: 9946

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1040

European-Non Finnish (NFE) AF: 0.00000216 AC: 1 AN: 463528

Other (OTH) AF: 0.00 AC: 0 AN: 16428

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.30
CADD	Benign	19
DANN	Benign	0.82
PhyloP100		2.6
PromoterAI		-0.12	Neutral

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: rs41477046; hg19: chr13-31040185;