NM_002121.6:c.47C>T

Variant names:

• chr6-33076088-C-T
• rs41558014
• NM_002121.6:c.47C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_002121.6(HLA-DPB1):​c.47C>T​(p.Thr16Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00129 in 1,612,310 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0036 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (34 hom.)
• Consequence: HLA-DPB1 NM_002121.6 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.12
• Publications: 8 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0032263398).
• BP6: Variant 6-33076088-C-T is Benign according to our data. Variant chr6-33076088-C-T is described in ClinVar as Benign. ClinVar VariationId is 725737.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00357 (543/152286) while in subpopulation EAS AF = 0.0257 (133/5180). AF 95% confidence interval is 0.0221. There are 3 homozygotes in GnomAd4. There are 281 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002121.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLA-DPB1	NM_002121.6	MANE Select	c.47C>T	p.Thr16Met	missense	Exon 1 of 6	NP_002112.3
	HLA-DPA1	NM_001242524.2		c.-99-2419G>A		intron	N/A	NP_001229453.1	P20036
	HLA-DPA1	NM_001242525.2		c.-23-2495G>A		intron	N/A	NP_001229454.1	X5CKE2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLA-DPB1	ENST00000418931.7	TSL:6 MANE Select	c.47C>T	p.Thr16Met	missense	Exon 1 of 6	ENSP00000408146.2	P04440
	HLA-DPB1	ENST00000714454.1		c.-266C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 7	ENSP00000519716.1	A0AAQ5BI07
	HLA-DPB1	ENST00000966804.1		c.47C>T	p.Thr16Met	missense	Exon 1 of 7	ENSP00000636863.1

Frequencies

GnomAD3 genomes AF: 0.00355 AC: 540 AN: 152168 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00830

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0258

Gnomad SAS AF: 0.00807

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00321 AC: 782 AN: 243912 AF XY: 0.00326

Gnomad AFR exome AF: 0.00680

Gnomad AMR exome AF: 0.000787

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0251

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000366

Gnomad OTH exome AF: 0.00167

GnomAD4 exome AF: 0.00105 AC: 1540 AN: 1460024 Hom.: 34 Cov.: 30 AF XY: 0.00124 AC XY: 897 AN XY: 726234

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

African (AFR) AF: 0.00682 AC: 228 AN: 33450

American (AMR) AF: 0.000873 AC: 39 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26102

East Asian (EAS) AF: 0.0121 AC: 478 AN: 39660

South Asian (SAS) AF: 0.00610 AC: 524 AN: 85972

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52262

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.0000252 AC: 28 AN: 1111790

Other (OTH) AF: 0.00396 AC: 239 AN: 60340

⚠️ 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: 0.00357 AC: 543 AN: 152286 Hom.: 3 Cov.: 32 AF XY: 0.00377 AC XY: 281 AN XY: 74450

African (AFR) AF: 0.00835 AC: 347 AN: 41560

American (AMR) AF: 0.000915 AC: 14 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0257 AC: 133 AN: 5180

South Asian (SAS) AF: 0.00808 AC: 39 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68010

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

Alfa AF: 0.00156 Hom.: 4

Bravo AF: 0.00391

ESP6500AA AF: 0.00861 AC: 26

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00302 AC: 355

Asia WGS AF: 0.0190 AC: 65 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.0050
DANN	Benign	0.70
DEOGEN2	Benign	0.018	T
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.0018	N
MetaRNN	Benign	0.0032	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.30	N
PhyloP100		-2.1
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.022
Sift	Benign	0.36	T
Sift4G	Benign	0.31	T
Polyphen		0.013	B
Vest4		0.054
MVP		0.085
MPC		0.78
ClinPred		0.011	T
GERP RS		-6.5
PromoterAI		-0.0094	Neutral
Varity_R		0.015
gMVP		0.40
Mutation Taster		=100/0	polymorphism

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: rs41558014; hg19: chr6-33043865;