Genetic Variant NM_002122.5:c.225C>A (chr6-32641452-C-A) – 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.225C>A(p.Ser75Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/19 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 0.022 ( 107 hom., cov: 13)

Exomes 𝑓: 0.011 ( 3978 hom. )

Failed GnomAD Quality Control

Consequence

HLA-DQA1
NM_002122.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.21

Publications

11 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=0.002570182).

BS2

High Homozygotes in GnomAd4 at 107 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-DQA1	NM_002122.5 link	c.225C>A	p.Ser75Arg	missense_variant	Exon 2 of 5	ENST00000343139.11	NP_002113.2	P01909A0A173ADG5Q8MH44
HLA-DQA1	XM_006715079.5 link	c.225C>A	p.Ser75Arg	missense_variant	Exon 2 of 4		XP_006715142.1
HLA-DQA1-AS1	XR_007059544.1 link	n.-142G>T		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLA-DQA1	ENST00000343139.11 link	c.225C>A	p.Ser75Arg	missense_variant	Exon 2 of 5	6	NM_002122.5	ENSP00000339398.5		P01909

Frequencies

GnomAD3 genomes

AF:

0.0219

AC:

1712

AN:

78132

Hom.:

107

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0210

Gnomad AMI

AF:

0.0219

Gnomad AMR

AF:

0.0202

Gnomad ASJ

AF:

0.0245

Gnomad EAS

AF:

0.0123

Gnomad SAS

AF:

0.0147

Gnomad FIN

AF:

0.0118

Gnomad MID

AF:

0.0431

Gnomad NFE

AF:

0.0255

Gnomad OTH

AF:

0.0262

GnomAD2 exomes

AF:

0.130

AC:

21202

AN:

163220

AF XY:

0.129

show subpopulations

Gnomad AFR exome

AF:

0.140

Gnomad AMR exome

AF:

0.186

Gnomad ASJ exome

AF:

0.101

Gnomad EAS exome

AF:

0.119

Gnomad FIN exome

AF:

0.117

Gnomad NFE exome

AF:

0.137

Gnomad OTH exome

AF:

0.0956

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0108

AC:

9846

AN:

915470

Hom.:

3978

Cov.:

AF XY:

0.0126

AC XY:

5765

AN XY:

458564

show subpopulations

African (AFR)

AF:

0.0106

AC:

253

AN:

23760

American (AMR)

AF:

0.0408

AC:

777

AN:

19034

Ashkenazi Jewish (ASJ)

AF:

0.0171

AC:

257

AN:

15062

East Asian (EAS)

AF:

0.0124

AC:

319

AN:

25680

South Asian (SAS)

AF:

0.0252

AC:

1559

AN:

61944

European-Finnish (FIN)

AF:

0.0172

AC:

631

AN:

36672

Middle Eastern (MID)

AF:

0.0343

AC:

108

AN:

3152

European-Non Finnish (NFE)

AF:

0.00801

AC:

5540

AN:

691712

Other (OTH)

AF:

0.0105

AC:

402

AN:

38454

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

166

248

331

414

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

126

168

210

<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:

0.0219

AC:

1710

AN:

78214

Hom.:

107

Cov.:

AF XY:

0.0207

AC XY:

787

AN XY:

38044

show subpopulations

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

African (AFR)

AF:

0.0209

AC:

474

AN:

22658

American (AMR)

AF:

0.0201

AC:

127

AN:

6332

Ashkenazi Jewish (ASJ)

AF:

0.0245

AC:

AN:

1592

East Asian (EAS)

AF:

0.0119

AC:

AN:

2514

South Asian (SAS)

AF:

0.0143

AC:

AN:

2592

European-Finnish (FIN)

AF:

0.0118

AC:

AN:

5944

Middle Eastern (MID)

AF:

0.0455

AC:

AN:

110

European-Non Finnish (NFE)

AF:

0.0255

AC:

891

AN:

34994

Other (OTH)

AF:

0.0266

AC:

AN:

976

⚠️ 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

172

344

515

687

859

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<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:

0.253

AC:

28495

Asia WGS

AF:

0.251

AC:

863

AN:

3442

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.67

CADD

Benign

7.9

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.011

.;.;T;.

Eigen

Benign

-0.97

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.046

LIST_S2

Benign

0.67

.;.;T;T

MetaRNN

Benign

0.0026

T;T;T;T

MetaSVM

Benign

-0.92

PhyloP100

-1.2

PrimateAI

Benign

0.31

PROVEAN

Uncertain

-2.8

D;D;D;D

REVEL

Benign

0.028

Sift

Benign

0.19

T;T;T;T

Sift4G

Benign

0.10

T;T;T;T

Vest4

0.12

MutPred

0.34

Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);

MPC

0.96

ClinPred

0.0059

GERP RS

-0.34

gMVP

0.41

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