13-30461330-GAAA-GAAAA

Variant names:

• chr13-30461330-G-GA
• rs41376448
• NM_002128.7:c.*26dupT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_002128.7(HMGB1):​c.*26dupT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.20 (3496 hom., cov: 17)
  • Exomes 𝑓: 0.22 (8133 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: Benign. The variant received -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.26 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMGB1	NM_002128.7	MANE Select	c.*26dupT		3_prime_UTR	Exon 5 of 5	NP_002119.1
	HMGB1	NM_001313892.2		c.*26dupT		3_prime_UTR	Exon 5 of 5	NP_001300821.1
	HMGB1	NM_001313893.1		c.*26dupT		3_prime_UTR	Exon 5 of 5	NP_001300822.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMGB1	ENST00000341423.10	TSL:1 MANE Select	c.*26dupT		3_prime_UTR	Exon 5 of 5	ENSP00000345347.5
	HMGB1	ENST00000399489.5	TSL:1	c.*247dupT		3_prime_UTR	Exon 5 of 5	ENSP00000382412.1
	HMGB1	ENST00000339872.8	TSL:2	c.*26dupT		3_prime_UTR	Exon 5 of 5	ENSP00000343040.4

Frequencies

GnomAD3 genomes AF: 0.202 AC: 29513 AN: 146150 Hom.: 3491 Cov.: 17

Gnomad AFR AF: 0.0780

Gnomad AMI AF: 0.259

Gnomad AMR AF: 0.169

Gnomad ASJ AF: 0.178

Gnomad EAS AF: 0.213

Gnomad SAS AF: 0.146

Gnomad FIN AF: 0.360

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.263

Gnomad OTH AF: 0.180

GnomAD2 exomes AF: 0.263 AC: 37162 AN: 141356 AF XY: 0.263

Gnomad AFR exome AF: 0.114

Gnomad AMR exome AF: 0.235

Gnomad ASJ exome AF: 0.259

Gnomad EAS exome AF: 0.257

Gnomad FIN exome AF: 0.344

Gnomad NFE exome AF: 0.280

Gnomad OTH exome AF: 0.280

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.217 AC: 267177 AN: 1229630 Hom.: 8133 Cov.: 32 AF XY: 0.216 AC XY: 130900 AN XY: 605748

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

African (AFR) AF: 0.0643 AC: 1739 AN: 27042

American (AMR) AF: 0.169 AC: 4550 AN: 26844

Ashkenazi Jewish (ASJ) AF: 0.184 AC: 3340 AN: 18144

East Asian (EAS) AF: 0.191 AC: 6276 AN: 32852

South Asian (SAS) AF: 0.157 AC: 9647 AN: 61462

European-Finnish (FIN) AF: 0.320 AC: 14210 AN: 44378

Middle Eastern (MID) AF: 0.144 AC: 468 AN: 3240

European-Non Finnish (NFE) AF: 0.224 AC: 216063 AN: 965606

Other (OTH) AF: 0.217 AC: 10884 AN: 50062

⚠️ 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: 0.202 AC: 29518 AN: 146236 Hom.: 3496 Cov.: 17 AF XY: 0.202 AC XY: 14360 AN XY: 71182

African (AFR) AF: 0.0779 AC: 2998 AN: 38508

American (AMR) AF: 0.169 AC: 2511 AN: 14900

Ashkenazi Jewish (ASJ) AF: 0.178 AC: 612 AN: 3430

East Asian (EAS) AF: 0.213 AC: 1089 AN: 5108

South Asian (SAS) AF: 0.146 AC: 687 AN: 4714

European-Finnish (FIN) AF: 0.360 AC: 3372 AN: 9378

Middle Eastern (MID) AF: 0.123 AC: 36 AN: 292

European-Non Finnish (NFE) AF: 0.263 AC: 17605 AN: 66988

Other (OTH) AF: 0.186 AC: 375 AN: 2018

Alfa AF: 0.134 Hom.: 277

Bravo AF: 0.182

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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

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: rs41376448; hg19: chr13-31035467; COSMIC: COSV58104284; COSMIC: COSV58104284;