Genetic Variant HLA-DQA1:p.Asp184Glu (chr6-32642192-T-G) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_002122.5(HLA-DQA1):c.552T>G(p.Asp184Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/18 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 0.018 ( 16 hom., cov: 16)

Exomes 𝑓: 0.079 ( 14160 hom. )

Failed GnomAD Quality Control

Consequence

HLA-DQA1
NM_002122.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.16

Publications

23 publications found

Variant links:

Genes affected

HLA-DQA1 (HGNC:4942): (major histocompatibility complex, class II, DQ alpha 1) HLA-DQA1 belongs to the HLA class II alpha chain paralogues. The class II molecule is a heterodimer consisting of an alpha (DQA) and a beta chain (DQB), 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. It is encoded by 5 exons; exon 1 encodes the leader peptide, exons 2 and 3 encode the two extracellular domains, and exon 4 encodes the transmembrane domain and the cytoplasmic tail. Within the DQ molecule both the alpha chain and the beta chain contain the polymorphisms specifying the peptide binding specificities, resulting in up to four different molecules. Typing for these polymorphisms is routinely done for bone marrow transplantation. [provided by RefSeq, Jul 2008]

HLA-DQA1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0018129051).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-DQA1	NM_002122.5 link	c.552T>G	p.Asp184Glu	missense_variant	Exon 3 of 5	ENST00000343139.11	NP_002113.2	P01909A0A173ADG5Q8MH44
HLA-DQA1	XM_006715079.5 link	c.552T>G	p.Asp184Glu	missense_variant	Exon 3 of 4		XP_006715142.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLA-DQA1	ENST00000343139.11 link	c.552T>G	p.Asp184Glu	missense_variant	Exon 3 of 5	6	NM_002122.5	ENSP00000339398.5		P01909

Frequencies

GnomAD3 genomes

AF:

0.0175

AC:

1571

AN:

89682

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0137

Gnomad AMI

AF:

0.00825

Gnomad AMR

AF:

0.0168

Gnomad ASJ

AF:

0.0272

Gnomad EAS

AF:

0.00886

Gnomad SAS

AF:

0.0172

Gnomad FIN

AF:

0.00888

Gnomad MID

AF:

0.0303

Gnomad NFE

AF:

0.0220

Gnomad OTH

AF:

0.0113

GnomAD2 exomes

AF:

0.165

AC:

33775

AN:

204164

AF XY:

0.169

show subpopulations

Gnomad AFR exome

AF:

0.121

Gnomad AMR exome

AF:

0.207

Gnomad ASJ exome

AF:

0.236

Gnomad EAS exome

AF:

0.122

Gnomad FIN exome

AF:

0.0964

Gnomad NFE exome

AF:

0.166

Gnomad OTH exome

AF:

0.175

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0790

AC:

85290

AN:

1079034

Hom.:

14160

Cov.:

AF XY:

0.0834

AC XY:

45110

AN XY:

540736

show subpopulations

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

African (AFR)

AF:

0.0589

AC:

1525

AN:

25888

American (AMR)

AF:

0.160

AC:

5985

AN:

37380

Ashkenazi Jewish (ASJ)

AF:

0.140

AC:

2786

AN:

19884

East Asian (EAS)

AF:

0.0519

AC:

1749

AN:

33728

South Asian (SAS)

AF:

0.137

AC:

9254

AN:

67700

European-Finnish (FIN)

AF:

0.0544

AC:

2446

AN:

44974

Middle Eastern (MID)

AF:

0.125

AC:

502

AN:

4022

European-Non Finnish (NFE)

AF:

0.0716

AC:

57238

AN:

799794

Other (OTH)

AF:

0.0833

AC:

3805

AN:

45664

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.353

Heterozygous variant carriers

3028

6055

9083

12110

15138

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0175

AC:

1573

AN:

89768

Hom.:

Cov.:

AF XY:

0.0158

AC XY:

693

AN XY:

43800

show subpopulations

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

African (AFR)

AF:

0.0137

AC:

349

AN:

25472

American (AMR)

AF:

0.0167

AC:

130

AN:

7762

Ashkenazi Jewish (ASJ)

AF:

0.0272

AC:

AN:

1912

East Asian (EAS)

AF:

0.00922

AC:

AN:

2930

South Asian (SAS)

AF:

0.0172

AC:

AN:

3084

European-Finnish (FIN)

AF:

0.00888

AC:

AN:

6756

Middle Eastern (MID)

AF:

0.0317

AC:

AN:

126

European-Non Finnish (NFE)

AF:

0.0220

AC:

880

AN:

39950

Other (OTH)

AF:

0.0111

AC:

AN:

1170

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.287

Heterozygous variant carriers

156

313

469

626

782

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.198

Hom.:

762

ESP6500AA

AF:

0.128

AC:

387

ESP6500EA

AF:

0.155

AC:

838

ExAC

AF:

0.202

AC:

23609

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.61

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.00020

.;.;T;.

Eigen

Benign

-0.44

Eigen_PC

Benign

-0.44

FATHMM_MKL

Benign

0.33

LIST_S2

Benign

0.71

.;.;T;T

MetaRNN

Benign

0.0018

T;T;T;T

MetaSVM

Benign

-0.97

PhyloP100

-1.2

PrimateAI

Benign

0.46

PROVEAN

Benign

0.24

N;N;N;N

REVEL

Benign

0.080

Sift

Benign

0.61

T;T;T;T

Sift4G

Benign

1.0

T;T;T;T

Vest4

0.088

MutPred

0.45

Gain of solvent accessibility (P = 0.1014);Gain of solvent accessibility (P = 0.1014);Gain of solvent accessibility (P = 0.1014);Gain of solvent accessibility (P = 0.1014);

MPC

0.78

ClinPred

0.0021

GERP RS

-0.81

gMVP

0.66

Mutation Taster

=97/3

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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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6-32642192-T-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over