Genetic Variant HLA-DQA1:p.Arg70Arg (chr6-32641435-C-A) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP7

The NM_002122.5(HLA-DQA1):c.208C>A(p.Arg70Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0015 ( 1 hom., cov: 13)

Exomes 𝑓: 0.0034 ( 393 hom. )

Failed GnomAD Quality Control

Consequence

HLA-DQA1
NM_002122.5 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.255

Publications

16 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: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.66).

BP7

Synonymous conserved (PhyloP=-0.255 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-DQA1	NM_002122.5 link	c.208C>A	p.Arg70Arg	synonymous_variant	Exon 2 of 5	ENST00000343139.11	NP_002113.2	P01909A0A173ADG5Q8MH44
HLA-DQA1	XM_006715079.5 link	c.208C>A	p.Arg70Arg	synonymous_variant	Exon 2 of 4		XP_006715142.1
HLA-DQA1-AS1	XR_007059544.1 link	n.-125G>T		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLA-DQA1	ENST00000343139.11 link	c.208C>A	p.Arg70Arg	synonymous_variant	Exon 2 of 5	6	NM_002122.5	ENSP00000339398.5		P01909

Frequencies

GnomAD3 genomes

AF:

0.00148

AC:

114

AN:

77196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00147

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00129

Gnomad ASJ

AF:

0.00118

Gnomad EAS

AF:

0.000780

Gnomad SAS

AF:

0.00168

Gnomad FIN

AF:

0.000690

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00170

Gnomad OTH

AF:

0.00211

GnomAD2 exomes

AF:

0.0107

AC:

1799

AN:

167538

AF XY:

0.0110

show subpopulations

Gnomad AFR exome

AF:

0.0147

Gnomad AMR exome

AF:

0.00709

Gnomad ASJ exome

AF:

0.0127

Gnomad EAS exome

AF:

0.00509

Gnomad FIN exome

AF:

0.00393

Gnomad NFE exome

AF:

0.0135

Gnomad OTH exome

AF:

0.00823

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00342

AC:

3154

AN:

923200

Hom.:

393

Cov.:

AF XY:

0.00400

AC XY:

1857

AN XY:

464830

show subpopulations

African (AFR)

AF:

0.00317

AC:

AN:

23980

American (AMR)

AF:

0.0107

AC:

231

AN:

21682

Ashkenazi Jewish (ASJ)

AF:

0.00818

AC:

129

AN:

15762

East Asian (EAS)

AF:

0.00174

AC:

AN:

26382

South Asian (SAS)

AF:

0.00829

AC:

534

AN:

64424

European-Finnish (FIN)

AF:

0.00186

AC:

AN:

38784

Middle Eastern (MID)

AF:

0.00326

AC:

AN:

3370

European-Non Finnish (NFE)

AF:

0.00279

AC:

1924

AN:

689948

Other (OTH)

AF:

0.00337

AC:

131

AN:

38868

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.406

Heterozygous variant carriers

101

202

302

403

504

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.00148

AC:

114

AN:

77282

Hom.:

Cov.:

AF XY:

0.00157

AC XY:

AN XY:

37594

show subpopulations

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

African (AFR)

AF:

0.00147

AC:

AN:

21842

American (AMR)

AF:

0.00129

AC:

AN:

6192

Ashkenazi Jewish (ASJ)

AF:

0.00118

AC:

AN:

1690

East Asian (EAS)

AF:

0.000784

AC:

AN:

2552

South Asian (SAS)

AF:

0.00168

AC:

AN:

2384

European-Finnish (FIN)

AF:

0.000690

AC:

AN:

5798

Middle Eastern (MID)

AF:

0.00

AC:

AN:

104

European-Non Finnish (NFE)

AF:

0.00170

AC:

AN:

35286

Other (OTH)

AF:

0.00206

AC:

AN:

970

⚠️ 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: 0.250

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0238

Hom.:

319

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.66

CADD

Benign

2.1

(source)

DANN

Benign

0.59

PhyloP100

-0.26

Mutation Taster

=100/0

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over