rs2308911

Variant names:

• chr6-33069803-T-G
• rs2308911
• ENST00000692443.1:c.184A>C

Variant summary

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

The ENST00000692443.1(HLA-DPA1):​c.184A>C​(p.Met62Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.204 in 1,579,094 control chromosomes in the GnomAD database, including 45,154 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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 0.28 (8068 hom., cov: 32)
  • Exomes 𝑓: 0.20 (37086 hom.)
• Consequence: HLA-DPA1 ENST00000692443.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.58
• Publications: 20 publications found

Genes affected

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=2.9242078E-6).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.643 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-DPA1	NM_001242524.2	c.184A>C	p.Met62Leu	missense_variant	Exon 3 of 6		NP_001229453.1
HLA-DPA1	NM_001242525.2	c.184A>C	p.Met62Leu	missense_variant	Exon 3 of 6		NP_001229454.1
HLA-DPA1	NM_001405020.1	c.184A>C	p.Met62Leu	missense_variant	Exon 2 of 4		NP_001391949.1
HLA-DPA1	NM_033554.4	c.184A>C	p.Met62Leu	missense_variant	Exon 2 of 5		NP_291032.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLA-DPA1	ENST00000692443.1	c.184A>C	p.Met62Leu	missense_variant	Exon 2 of 5			ENSP00000509163.1

Frequencies

GnomAD3 genomes AF: 0.285 AC: 43197 AN: 151830 Hom.: 8052 Cov.: 32

Gnomad AFR AF: 0.486

Gnomad AMI AF: 0.143

Gnomad AMR AF: 0.243

Gnomad ASJ AF: 0.168

Gnomad EAS AF: 0.661

Gnomad SAS AF: 0.336

Gnomad FIN AF: 0.103

Gnomad MID AF: 0.175

Gnomad NFE AF: 0.175

Gnomad OTH AF: 0.299

GnomAD2 exomes AF: 0.232 AC: 55816 AN: 240502 AF XY: 0.230

Gnomad AFR exome AF: 0.498

Gnomad AMR exome AF: 0.163

Gnomad ASJ exome AF: 0.168

Gnomad EAS exome AF: 0.655

Gnomad FIN exome AF: 0.0982

Gnomad NFE exome AF: 0.162

Gnomad OTH exome AF: 0.197

GnomAD4 exome AF: 0.196 AC: 279366 AN: 1427146 Hom.: 37086 Cov.: 33 AF XY: 0.199 AC XY: 141150 AN XY: 711022

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

African (AFR) AF: 0.507 AC: 16358 AN: 32256

American (AMR) AF: 0.184 AC: 8163 AN: 44462

Ashkenazi Jewish (ASJ) AF: 0.172 AC: 4446 AN: 25786

East Asian (EAS) AF: 0.622 AC: 24551 AN: 39442

South Asian (SAS) AF: 0.307 AC: 25982 AN: 84502

European-Finnish (FIN) AF: 0.102 AC: 5346 AN: 52204

Middle Eastern (MID) AF: 0.199 AC: 1136 AN: 5700

European-Non Finnish (NFE) AF: 0.166 AC: 180157 AN: 1083706

Other (OTH) AF: 0.224 AC: 13227 AN: 59088

⚠️ 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: 0.285 AC: 43242 AN: 151948 Hom.: 8068 Cov.: 32 AF XY: 0.282 AC XY: 20953 AN XY: 74284

African (AFR) AF: 0.486 AC: 20107 AN: 41386

American (AMR) AF: 0.243 AC: 3710 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.168 AC: 582 AN: 3466

East Asian (EAS) AF: 0.662 AC: 3412 AN: 5156

South Asian (SAS) AF: 0.335 AC: 1608 AN: 4798

European-Finnish (FIN) AF: 0.103 AC: 1086 AN: 10580

Middle Eastern (MID) AF: 0.182 AC: 53 AN: 292

European-Non Finnish (NFE) AF: 0.175 AC: 11915 AN: 67986

Other (OTH) AF: 0.305 AC: 639 AN: 2098

Alfa AF: 0.234 Hom.: 5052

Bravo AF: 0.303

ESP6500AA AF: 0.0149 AC: 45

ESP6500EA AF: 0.00129 AC: 7

ExAC AF: 0.239 AC: 28100

Asia WGS AF: 0.432 AC: 1503 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	0.0010
DANN	Benign	0.24
DEOGEN2	Benign	0.00051	T;.
Eigen	Benign	-2.2
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.0089	N
MetaRNN	Benign	0.0000029	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.015	N;.
PhyloP100		-2.6
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.13	N;N
REVEL	Benign	0.063
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;.
Polyphen		0.0	B;.
Vest4		0.075
MutPred		0.066		Gain of phosphorylation at Y64 (P = 0.0928);Gain of phosphorylation at Y64 (P = 0.0928);
MPC		0.44
ClinPred		0.0000096	T
GERP RS		-6.0
Varity_R		0.24
gMVP		0.31
Mutation Taster		=98/2	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: rs2308911; hg19: chr6-33037580; COSMIC: COSV70089069; COSMIC: COSV70089069;