chr13-30461330-G-GAA

Variant names:

• chr13-30461330-G-GAA
• rs41376448
• NM_002128.7:c.*25_*26dupTT

Variant summary

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

The NM_002128.7(HMGB1):​c.*25_*26dupTT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 17)
  • Exomes 𝑓: 0.0038 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HMGB1 NM_002128.7 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0750
• Publications: 6 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMGB1	NM_002128.7	c.*25_*26dupTT		3_prime_UTR_variant	Exon 5 of 5	ENST00000341423.10	NP_002119.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HMGB1	ENST00000341423.10	c.*25_*26dupTT		3_prime_UTR_variant	Exon 5 of 5	1	NM_002128.7	ENSP00000345347.5

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 24 AN: 146240 Hom.: 0 Cov.: 17

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000134

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00176

Gnomad SAS AF: 0.000212

Gnomad FIN AF: 0.000531

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000895

Gnomad OTH AF: 0.000499

GnomAD2 exomes AF: 0.00384 AC: 543 AN: 141356 AF XY: 0.00345

Gnomad AFR exome AF: 0.00215

Gnomad AMR exome AF: 0.00442

Gnomad ASJ exome AF: 0.00318

Gnomad EAS exome AF: 0.00672

Gnomad FIN exome AF: 0.00433

Gnomad NFE exome AF: 0.00366

Gnomad OTH exome AF: 0.00325

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00376 AC: 4907 AN: 1306418 Hom.: 0 Cov.: 32 AF XY: 0.00370 AC XY: 2382 AN XY: 643580

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000571 AC: 16 AN: 28030

American (AMR) AF: 0.00264 AC: 76 AN: 28826

Ashkenazi Jewish (ASJ) AF: 0.00265 AC: 52 AN: 19612

East Asian (EAS) AF: 0.00393 AC: 140 AN: 35652

South Asian (SAS) AF: 0.00249 AC: 166 AN: 66534

European-Finnish (FIN) AF: 0.00877 AC: 399 AN: 45472

Middle Eastern (MID) AF: 0.00114 AC: 4 AN: 3520

European-Non Finnish (NFE) AF: 0.00378 AC: 3874 AN: 1025538

Other (OTH) AF: 0.00338 AC: 180 AN: 53234

⚠️ 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 AF: 0.000164 AC: 24 AN: 146326 Hom.: 0 Cov.: 17 AF XY: 0.000225 AC XY: 16 AN XY: 71246

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 38520

American (AMR) AF: 0.000134 AC: 2 AN: 14904

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3434

East Asian (EAS) AF: 0.00176 AC: 9 AN: 5110

South Asian (SAS) AF: 0.000212 AC: 1 AN: 4714

European-Finnish (FIN) AF: 0.000531 AC: 5 AN: 9408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000895 AC: 6 AN: 67020

Other (OTH) AF: 0.000495 AC: 1 AN: 2022

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0000000000172907), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 277

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.075
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs41376448; hg19: chr13-31035467;