NM_002121.6:c.313A>G

Variant names:

• chr6-33080884-A-G
• rs1042151
• NM_002121.6:c.313A>G

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.313A>G​(p.Met105Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.198 in 1,595,966 control chromosomes in the GnomAD database, including 34,695 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.24 (4997 hom., cov: 31)
  • Exomes 𝑓: 0.19 (29698 hom.)
• Consequence: HLA-DPB1 NM_002121.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.94
• Publications: 60 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]

HLA-DPA1 (HGNC:4938): (major histocompatibility complex, class II, DP alpha 1) HLA-DPA1 belongs to the HLA class II alpha chain paralogues. This class II molecule is a heterodimer consisting of an alpha (DPA) and a beta (DPB) chain, 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 alpha chain is approximately 33-35 kDa and its gene contains 5 exons. Exon one encodes the leader peptide, exons 2 and 3 encode the two extracellular domains, exon 4 encodes the transmembrane domain and 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 (MetaRNN=0.007756591).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.366 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-DPB1	NM_002121.6	c.313A>G	p.Met105Val	missense_variant	Exon 2 of 6	ENST00000418931.7	NP_002112.3
HLA-DPA1	NM_001242524.2	c.-304T>C		upstream_gene_variant			NP_001229453.1
HLA-DPA1	NM_001242525.2	c.-228T>C		upstream_gene_variant			NP_001229454.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLA-DPB1	ENST00000418931.7	c.313A>G	p.Met105Val	missense_variant	Exon 2 of 6	6	NM_002121.6	ENSP00000408146.2

Frequencies

GnomAD3 genomes AF: 0.242 AC: 36728 AN: 151838 Hom.: 4993 Cov.: 31

Gnomad AFR AF: 0.371

Gnomad AMI AF: 0.117

Gnomad AMR AF: 0.199

Gnomad ASJ AF: 0.119

Gnomad EAS AF: 0.123

Gnomad SAS AF: 0.223

Gnomad FIN AF: 0.204

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.198

Gnomad OTH AF: 0.236

GnomAD2 exomes AF: 0.176 AC: 42052 AN: 238938 AF XY: 0.176

Gnomad AFR exome AF: 0.375

Gnomad AMR exome AF: 0.126

Gnomad ASJ exome AF: 0.102

Gnomad EAS exome AF: 0.0896

Gnomad FIN exome AF: 0.172

Gnomad NFE exome AF: 0.175

Gnomad OTH exome AF: 0.169

GnomAD4 exome AF: 0.193 AC: 279305 AN: 1444010 Hom.: 29698 Cov.: 38 AF XY: 0.193 AC XY: 138963 AN XY: 718744

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

African (AFR) AF: 0.396 AC: 13188 AN: 33342

American (AMR) AF: 0.144 AC: 6397 AN: 44332

Ashkenazi Jewish (ASJ) AF: 0.121 AC: 3118 AN: 25792

East Asian (EAS) AF: 0.134 AC: 5327 AN: 39618

South Asian (SAS) AF: 0.217 AC: 18571 AN: 85548

European-Finnish (FIN) AF: 0.194 AC: 10050 AN: 51764

Middle Eastern (MID) AF: 0.177 AC: 1010 AN: 5716

European-Non Finnish (NFE) AF: 0.191 AC: 209686 AN: 1098168

Other (OTH) AF: 0.200 AC: 11958 AN: 59730

⚠️ 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: 0.242 AC: 36746 AN: 151956 Hom.: 4997 Cov.: 31 AF XY: 0.238 AC XY: 17696 AN XY: 74290

African (AFR) AF: 0.371 AC: 15345 AN: 41394

American (AMR) AF: 0.199 AC: 3047 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.119 AC: 413 AN: 3466

East Asian (EAS) AF: 0.122 AC: 628 AN: 5148

South Asian (SAS) AF: 0.222 AC: 1065 AN: 4806

European-Finnish (FIN) AF: 0.204 AC: 2152 AN: 10572

Middle Eastern (MID) AF: 0.173 AC: 51 AN: 294

European-Non Finnish (NFE) AF: 0.198 AC: 13440 AN: 67950

Other (OTH) AF: 0.236 AC: 498 AN: 2108

Alfa AF: 0.202 Hom.: 12085

Bravo AF: 0.243

ExAC AF: 0.190 AC: 23002

Asia WGS AF: 0.244 AC: 849 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	0.0020
DANN	Benign	0.21
DEOGEN2	Benign	0.0088	T;T
Eigen	Benign	-2.4
Eigen_PC	Benign	-2.4
FATHMM_MKL	Benign	0.0028	N
MetaRNN	Benign	0.0078	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-2.6	N;.
PhyloP100		-3.9
PrimateAI	Benign	0.26	T
PROVEAN	Benign	1.3	N;N
REVEL	Uncertain	0.39
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;.
Vest4		0.0080
MPC		0.76
ClinPred		0.0080	T
GERP RS		-7.0
PromoterAI		-0.27	Neutral
Varity_R		0.17
gMVP		0.39
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: rs1042151; hg19: chr6-33048661; COSMIC: COSV69602522; COSMIC: COSV69602522;