chr13-30464004-T-TAA

Variant names:

• chr13-30464004-T-TAA
• rs41497949
• ENST00000399489.5:c.-326_-325dupTT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The ENST00000399489.5(HMGB1):​c.-326_-325dupTT variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00322 in 664,568 control chromosomes in the GnomAD database, including 13 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0033 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (10 hom.)
• Consequence: HMGB1 ENST00000399489.5 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.740
• 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 -8 ACMG points.

• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0032 (1638/512336) while in subpopulation MID AF = 0.0249 (27/1084). AF 95% confidence interval is 0.0176. There are 10 homozygotes in GnomAdExome4. There are 783 alleles in the male GnomAdExome4 subpopulation. Median coverage is 8. This position passed quality control check.
• BS2: High AC in GnomAd4 at 499 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000399489.5. 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.-14-312_-14-311dupTT		intron	N/A	NP_002119.1
	HMGB1	NM_001313892.2		c.-15+155_-15+156dupTT		intron	N/A	NP_001300821.1
	HMGB1	NM_001313893.1		c.-14-312_-14-311dupTT		intron	N/A	NP_001300822.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMGB1	ENST00000399489.5	TSL:1	c.-326_-325dupTT		5_prime_UTR	Exon 1 of 5	ENSP00000382412.1
	HMGB1	ENST00000341423.10	TSL:1 MANE Select	c.-14-312_-14-311dupTT		intron	N/A	ENSP00000345347.5
	HMGB1	ENST00000468384.1	TSL:1	n.120-312_120-311dupTT		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00328 AC: 499 AN: 152114 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00615

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0145

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00385

Gnomad OTH AF: 0.00288

GnomAD4 exome AF: 0.00320 AC: 1638 AN: 512336 Hom.: 10 Cov.: 8 AF XY: 0.00322 AC XY: 783 AN XY: 242802

African (AFR) AF: 0.000106 AC: 1 AN: 9424

American (AMR) AF: 0.00531 AC: 9 AN: 1694

Ashkenazi Jewish (ASJ) AF: 0.00307 AC: 12 AN: 3910

East Asian (EAS) AF: 0.00 AC: 0 AN: 3390

South Asian (SAS) AF: 0.0142 AC: 162 AN: 11390

European-Finnish (FIN) AF: 0.00112 AC: 1 AN: 892

Middle Eastern (MID) AF: 0.0249 AC: 27 AN: 1084

European-Non Finnish (NFE) AF: 0.00294 AC: 1360 AN: 463088

Other (OTH) AF: 0.00378 AC: 66 AN: 17464

GnomAD4 genome AF: 0.00328 AC: 499 AN: 152232 Hom.: 3 Cov.: 32 AF XY: 0.00372 AC XY: 277 AN XY: 74436

African (AFR) AF: 0.000578 AC: 24 AN: 41538

American (AMR) AF: 0.00614 AC: 94 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00490 AC: 17 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.0145 AC: 70 AN: 4822

European-Finnish (FIN) AF: 0.00132 AC: 14 AN: 10596

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.00385 AC: 262 AN: 68004

Other (OTH) AF: 0.00285 AC: 6 AN: 2108

Alfa AF: 0.00109 Hom.: 0

Bravo AF: 0.00324

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.74
Mutation Taster		=300/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs41497949; hg19: chr13-31038141;