chr6-33069802-A-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_033554.4(HLA-DPA1):c.185T>A(p.Met62Lys) 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 1,578,240 control chromosomes in the GnomAD database, including 45,122 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M62V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.28 ( 8070 hom., cov: 32)

Exomes 𝑓: 0.20 ( 37052 hom. )

Consequence

HLA-DPA1
NM_033554.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.575

Publications

17 publications found

Variant links:

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]

HLA-DPA1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=4.6335754E-6).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.643 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033554.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HLA-DPA1	NM_033554.4	MANE Select	c.185T>A	p.Met62Lys	missense	Exon 2 of 5	NP_291032.2
HLA-DPA1	NM_001242524.2		c.185T>A	p.Met62Lys	missense	Exon 3 of 6	NP_001229453.1	P20036
HLA-DPA1	NM_001242525.2		c.185T>A	p.Met62Lys	missense	Exon 3 of 6	NP_001229454.1	X5CKE2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HLA-DPA1	ENST00000692443.1	MANE Select	c.185T>A	p.Met62Lys	missense	Exon 2 of 5	ENSP00000509163.1	P20036
HLA-DPA1	ENST00000419277.5	TSL:6	c.185T>A	p.Met62Lys	missense	Exon 3 of 6	ENSP00000393566.1	P20036
HLA-DPA1	ENST00000923943.1		c.185T>A	p.Met62Lys	missense	Exon 3 of 6	ENSP00000594002.1

Frequencies

GnomAD3 genomes

AF:

0.284

AC:

43205

AN:

151874

Hom.:

8054

Cov.:

show subpopulations

Gnomad AFR

AF:

0.486

Gnomad AMI

AF:

0.143

Gnomad AMR

AF:

0.243

Gnomad ASJ

AF:

0.168

Gnomad EAS

AF:

0.660

Gnomad SAS

AF:

0.336

Gnomad FIN

AF:

0.103

Gnomad MID

AF:

0.174

Gnomad NFE

AF:

0.175

Gnomad OTH

AF:

0.298

GnomAD2 exomes

AF:

0.232

AC:

55850

AN:

240574

AF XY:

0.230

show subpopulations

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:

0.0984

Gnomad NFE exome

AF:

0.162

Gnomad OTH exome

AF:

0.197

GnomAD4 exome

AF:

0.196

AC:

278914

AN:

1426248

Hom.:

37052

Cov.:

AF XY:

0.198

AC XY:

140987

AN XY:

710698

show subpopulations

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

African (AFR)

AF:

0.507

AC:

16326

AN:

32212

American (AMR)

AF:

0.184

AC:

8161

AN:

44462

Ashkenazi Jewish (ASJ)

AF:

0.173

AC:

4456

AN:

25806

East Asian (EAS)

AF:

0.622

AC:

24553

AN:

39444

South Asian (SAS)

AF:

0.308

AC:

26009

AN:

84544

European-Finnish (FIN)

AF:

0.102

AC:

5347

AN:

52206

Middle Eastern (MID)

AF:

0.199

AC:

1133

AN:

5696

European-Non Finnish (NFE)

AF:

0.166

AC:

179716

AN:

1082820

Other (OTH)

AF:

0.224

AC:

13213

AN:

59058

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.354

Heterozygous variant carriers

9643

19286

28928

38571

48214

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6502

13004

19506

26008

32510

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.285

AC:

43250

AN:

151992

Hom.:

8070

Cov.:

AF XY:

0.282

AC XY:

20952

AN XY:

74308

show subpopulations

African (AFR)

AF:

0.486

AC:

20113

AN:

41408

American (AMR)

AF:

0.243

AC:

3710

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.168

AC:

582

AN:

3466

East Asian (EAS)

AF:

0.661

AC:

3412

AN:

5158

South Asian (SAS)

AF:

0.335

AC:

1608

AN:

4800

European-Finnish (FIN)

AF:

0.103

AC:

1086

AN:

10586

Middle Eastern (MID)

AF:

0.180

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.175

AC:

11916

AN:

67980

Other (OTH)

AF:

0.304

AC:

640

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1410

2819

4229

5638

7048

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

424

848

1272

1696

2120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.199

Hom.:

1164

Bravo

AF:

0.303

ESP6500AA

AF:

0.0175

AC:

ESP6500EA

AF:

0.00166

AC:

ExAC

AF:

0.239

AC:

28105

Asia WGS

AF:

0.432

AC:

1503

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.44

CADD

Benign

0.0010

(source)

DANN

Benign

0.56

DEOGEN2

Benign

0.013

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.019

MetaRNN

Benign

0.0000046

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.1

PhyloP100

-0.57

PrimateAI

Benign

0.30

PROVEAN

Uncertain

-2.4

REVEL

Uncertain

0.29

Sift

Benign

0.38

Sift4G

Benign

0.35

Polyphen

0.15

Vest4

0.14

MPC

1.2

ClinPred

0.023

GERP RS

-6.0

Varity_R

0.24

gMVP

0.71

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over