6-33086165-T-C

Variant names:

• chr6-33086165-T-C
• rs9277489
• NM_002121.6:c.758-54T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002121.6(HLA-DPB1):​c.758-54T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.19 in 1,338,954 control chromosomes in the GnomAD database, including 31,333 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 0.25 (5241 hom., cov: 31)
  • Exomes 𝑓: 0.18 (26092 hom.)
• Consequence: HLA-DPB1 NM_002121.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.118
• Publications: 30 publications found

Genes affected

HLA-DPB1 (HGNC:4940): (major histocompatibility complex, class II, DP beta 1) HLA-DPB belongs to the HLA class II beta chain paralogues. This class II molecule is a heterodimer consisting of an alpha (DPA) and a beta chain (DPB), both anchored in the membrane. It plays a central role in the immune system by presenting peptides derived from extracellular proteins. Class II molecules are expressed in antigen presenting cells (APC: B lymphocytes, dendritic cells, macrophages). The beta chain is approximately 26-28 kDa and its gene contains 6 exons. Exon one encodes the leader peptide, exons 2 and 3 encode the two extracellular domains, exon 4 encodes the transmembrane domain and exon 5 encodes the cytoplasmic tail. Within the DP molecule both the alpha chain and the beta chain contain the polymorphisms specifying the peptide binding specificities, resulting in up to 4 different molecules. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.608 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-DPB1	NM_002121.6	c.758-54T>C		intron_variant	Intron 4 of 5	ENST00000418931.7	NP_002112.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLA-DPB1	ENST00000418931.7	c.758-54T>C		intron_variant	Intron 4 of 5	6	NM_002121.6	ENSP00000408146.2

Frequencies

GnomAD3 genomes AF: 0.252 AC: 38273 AN: 151826 Hom.: 5228 Cov.: 31

Gnomad AFR AF: 0.243

Gnomad AMI AF: 0.103

Gnomad AMR AF: 0.235

Gnomad ASJ AF: 0.173

Gnomad EAS AF: 0.626

Gnomad SAS AF: 0.275

Gnomad FIN AF: 0.201

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.245

Gnomad OTH AF: 0.272

GnomAD4 exome AF: 0.182 AC: 216590 AN: 1187008 Hom.: 26092 AF XY: 0.188 AC XY: 113011 AN XY: 602180

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

African (AFR) AF: 0.195 AC: 4989 AN: 25580

American (AMR) AF: 0.189 AC: 8308 AN: 43988

Ashkenazi Jewish (ASJ) AF: 0.162 AC: 4009 AN: 24820

East Asian (EAS) AF: 0.583 AC: 21623 AN: 37114

South Asian (SAS) AF: 0.224 AC: 17969 AN: 80232

European-Finnish (FIN) AF: 0.203 AC: 10782 AN: 53042

Middle Eastern (MID) AF: 0.193 AC: 1031 AN: 5330

European-Non Finnish (NFE) AF: 0.159 AC: 137594 AN: 866194

Other (OTH) AF: 0.203 AC: 10285 AN: 50708

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.252 AC: 38301 AN: 151946 Hom.: 5241 Cov.: 31 AF XY: 0.249 AC XY: 18509 AN XY: 74274

African (AFR) AF: 0.243 AC: 10047 AN: 41414

American (AMR) AF: 0.235 AC: 3596 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.173 AC: 599 AN: 3468

East Asian (EAS) AF: 0.626 AC: 3230 AN: 5158

South Asian (SAS) AF: 0.273 AC: 1312 AN: 4812

European-Finnish (FIN) AF: 0.201 AC: 2128 AN: 10574

Middle Eastern (MID) AF: 0.238 AC: 70 AN: 294

European-Non Finnish (NFE) AF: 0.245 AC: 16632 AN: 67928

Other (OTH) AF: 0.282 AC: 593 AN: 2106

Alfa AF: 0.251 Hom.: 14133

Bravo AF: 0.253

Asia WGS AF: 0.403 AC: 1400 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	9.3
DANN	Benign	0.50
PhyloP100		-0.12
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: rs9277489; hg19: chr6-33053942; COSMIC: COSV69602692; COSMIC: COSV69602692;