Genetic Variant HLA-DQA1:p.Lys76Gln (chr6-32641453-A-C) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_002122.5(HLA-DQA1):c.226A>C(p.Lys76Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/19 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 0.021 ( 101 hom., cov: 13)

Exomes 𝑓: 0.010 ( 3727 hom. )

Failed GnomAD Quality Control

Consequence

HLA-DQA1
NM_002122.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.27

Publications

12 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:

HLA-DQA1-AS1 (HGNC:56667): (HLA-DQA1 antisense RNA 1)

HLA-DQA1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.015239656).

BS2

High Homozygotes in GnomAd4 at 101 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-DQA1	NM_002122.5 link	c.226A>C	p.Lys76Gln	missense_variant	Exon 2 of 5	ENST00000343139.11	NP_002113.2	P01909A0A173ADG5Q8MH44
HLA-DQA1	XM_006715079.5 link	c.226A>C	p.Lys76Gln	missense_variant	Exon 2 of 4		XP_006715142.1
HLA-DQA1-AS1	XR_007059544.1 link	n.-143T>G		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLA-DQA1	ENST00000343139.11 link	c.226A>C	p.Lys76Gln	missense_variant	Exon 2 of 5	6	NM_002122.5	ENSP00000339398.5		P01909

Frequencies

GnomAD3 genomes

AF:

0.0215

AC:

1675

AN:

77942

Hom.:

101

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0207

Gnomad AMI

AF:

0.0199

Gnomad AMR

AF:

0.0196

Gnomad ASJ

AF:

0.0246

Gnomad EAS

AF:

0.0118

Gnomad SAS

AF:

0.0145

Gnomad FIN

AF:

0.0114

Gnomad MID

AF:

0.0339

Gnomad NFE

AF:

0.0251

Gnomad OTH

AF:

0.0254

GnomAD2 exomes

AF:

0.128

AC:

20729

AN:

161970

AF XY:

0.127

show subpopulations

Gnomad AFR exome

AF:

0.138

Gnomad AMR exome

AF:

0.186

Gnomad ASJ exome

AF:

0.0975

Gnomad EAS exome

AF:

0.118

Gnomad FIN exome

AF:

0.114

Gnomad NFE exome

AF:

0.134

Gnomad OTH exome

AF:

0.0945

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0101

AC:

9206

AN:

915728

Hom.:

3727

Cov.:

AF XY:

0.0118

AC XY:

5408

AN XY:

458594

show subpopulations

African (AFR)

AF:

0.00981

AC:

233

AN:

23758

American (AMR)

AF:

0.0385

AC:

733

AN:

19044

Ashkenazi Jewish (ASJ)

AF:

0.0158

AC:

238

AN:

15042

East Asian (EAS)

AF:

0.0115

AC:

295

AN:

25668

South Asian (SAS)

AF:

0.0237

AC:

1468

AN:

61922

European-Finnish (FIN)

AF:

0.0161

AC:

590

AN:

36690

Middle Eastern (MID)

AF:

0.0321

AC:

101

AN:

3150

European-Non Finnish (NFE)

AF:

0.00748

AC:

5177

AN:

691992

Other (OTH)

AF:

0.00965

AC:

371

AN:

38462

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.628

Heterozygous variant carriers

158

236

315

394

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

160

200

<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:

0.0214

AC:

1673

AN:

78028

Hom.:

101

Cov.:

AF XY:

0.0203

AC XY:

770

AN XY:

37948

show subpopulations

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

African (AFR)

AF:

0.0206

AC:

467

AN:

22636

American (AMR)

AF:

0.0194

AC:

123

AN:

6332

Ashkenazi Jewish (ASJ)

AF:

0.0246

AC:

AN:

1586

East Asian (EAS)

AF:

0.0114

AC:

AN:

2534

South Asian (SAS)

AF:

0.0141

AC:

AN:

2556

European-Finnish (FIN)

AF:

0.0114

AC:

AN:

5990

Middle Eastern (MID)

AF:

0.0357

AC:

AN:

112

European-Non Finnish (NFE)

AF:

0.0250

AC:

872

AN:

34812

Other (OTH)

AF:

0.0258

AC:

AN:

968

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 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: 0.265

Heterozygous variant carriers

170

340

509

679

849

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.104

Hom.:

327

ExAC

AF:

0.254

AC:

28450

Asia WGS

AF:

0.252

AC:

863

AN:

3428

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.67

CADD

Benign

0.0050

(source)

DANN

Benign

0.084

DEOGEN2

Benign

0.0020

.;.;T;.

Eigen

Benign

-2.1

Eigen_PC

Benign

-2.2

FATHMM_MKL

Benign

0.016

LIST_S2

Benign

0.80

.;.;T;T

MetaRNN

Benign

0.015

T;T;T;T

MetaSVM

Benign

-0.96

PhyloP100

-2.3

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.63

N;N;N;N

REVEL

Benign

0.023

Sift

Benign

0.79

T;T;T;T

Sift4G

Benign

0.62

T;T;T;T

Vest4

0.043

MPC

0.89

ClinPred

0.0019

GERP RS

-8.0

gMVP

0.26

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over