chr6-33080884-A-G

Position:

• chr6-33080884-A-G

Variant summary

Our verdict is Benign. Variant got -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. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M105I) has been classified as Likely benign.

• 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

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

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
HLA-DPB1	NM_002121.6	c.313A>G	p.Met105Val	missense_variant	2/6	ENST00000418931.7	NP_002112.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HLA-DPB1	ENST00000418931.7	c.313A>G	p.Met105Val	missense_variant	2/6		NM_002121.6	ENSP00000408146	P1

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

GnomAD3 exomes AF: 0.176 AC: 42052 AN: 238938 Hom.: 4418 AF XY: 0.176 AC XY: 22831 AN XY: 129558

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 SAS exome AF: 0.211

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

Gnomad4 AFR exome AF: 0.396

Gnomad4 AMR exome AF: 0.144

Gnomad4 ASJ exome AF: 0.121

Gnomad4 EAS exome AF: 0.134

Gnomad4 SAS exome AF: 0.217

Gnomad4 FIN exome AF: 0.194

Gnomad4 NFE exome AF: 0.191

Gnomad4 OTH exome AF: 0.200

GnomAD4 genome AF: 0.242 AC: 36746 AN: 151956 Hom.: 4997 Cov.: 31 AF XY: 0.238 AC XY: 17696 AN XY: 74290

Gnomad4 AFR AF: 0.371

Gnomad4 AMR AF: 0.199

Gnomad4 ASJ AF: 0.119

Gnomad4 EAS AF: 0.122

Gnomad4 SAS AF: 0.222

Gnomad4 FIN AF: 0.204

Gnomad4 NFE AF: 0.198

Gnomad4 OTH AF: 0.236

Alfa AF: 0.196 Hom.: 4796

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;.
MutationTaster	Benign	1.0	P;P;P
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
Varity_R		0.17
gMVP		0.39

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

Publications

LitVar

Other links and lift over

dbSNP: rs1042151; hg19: chr6-33048661; COSMIC: COSV69602522; COSMIC: COSV69602522;