rs2308911

chr6-33069803-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001242525.2(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. 14/20 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. M62K) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.28 (8068 hom., cov: 32)
  • Exomes 𝑓: 0.20 (37086 hom.)
• Consequence: HLA-DPA1 NM_001242525.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.58

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

Verdict is Benign. Variant got -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/exons	MANE	UniProt
HLA-DPA1	NM_033554.4	c.184A>C	p.Met62Leu	missense_variant	2/5	ENST00000692443.1
HLA-DPA1	NM_001242525.2	c.184A>C	p.Met62Leu	missense_variant	3/6
HLA-DPA1	NM_001242524.2	c.184A>C	p.Met62Leu	missense_variant	3/6
HLA-DPA1	NM_001405020.1	c.184A>C	p.Met62Leu	missense_variant	2/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HLA-DPA1	ENST00000692443.1	c.184A>C	p.Met62Leu	missense_variant	2/5		NM_033554.4	P1

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

GnomAD3 exomes AF: 0.232 AC: 55816 AN: 240502 Hom.: 9863 AF XY: 0.230 AC XY: 30143 AN XY: 130920

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 SAS exome AF: 0.303

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

Gnomad4 AFR exome AF: 0.507

Gnomad4 AMR exome AF: 0.184

Gnomad4 ASJ exome AF: 0.172

Gnomad4 EAS exome AF: 0.622

Gnomad4 SAS exome AF: 0.307

Gnomad4 FIN exome AF: 0.102

Gnomad4 NFE exome AF: 0.166

Gnomad4 OTH exome AF: 0.224

GnomAD4 genome AF: 0.285 AC: 43242 AN: 151948 Hom.: 8068 Cov.: 32 AF XY: 0.282 AC XY: 20953 AN XY: 74284

Gnomad4 AFR AF: 0.486

Gnomad4 AMR AF: 0.243

Gnomad4 ASJ AF: 0.168

Gnomad4 EAS AF: 0.662

Gnomad4 SAS AF: 0.335

Gnomad4 FIN AF: 0.103

Gnomad4 NFE AF: 0.175

Gnomad4 OTH AF: 0.305

Alfa AF: 0.182 Hom.: 1741

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;.
MutationTaster	Benign	1.0	P;P
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

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: rs2308911; hg19: chr6-33037580; COSMIC: COSV70089069; COSMIC: COSV70089069;