6-32641349-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_002122.5(HLA-DQA1):c.122T>C(p.Phe41Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.23 ( 3842 hom., cov: 15)

Exomes 𝑓: 0.23 ( 68797 hom. )

Failed GnomAD Quality Control

Consequence

HLA-DQA1
NM_002122.5 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.905

Publications

57 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 -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.1289733E-5).

BP6

Variant 6-32641349-T-C is Benign according to our data. Variant chr6-32641349-T-C is described in ClinVar as [Benign]. Clinvar id is 1257290.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAd4 at 3842 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-DQA1	NM_002122.5 link	c.122T>C	p.Phe41Ser	missense_variant	Exon 2 of 5	ENST00000343139.11	NP_002113.2	P01909A0A173ADG5Q8MH44
HLA-DQA1	XM_006715079.5 link	c.122T>C	p.Phe41Ser	missense_variant	Exon 2 of 4		XP_006715142.1
HLA-DQA1-AS1	XR_007059544.1 link	n.-39A>G		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLA-DQA1	ENST00000343139.11 link	c.122T>C	p.Phe41Ser	missense_variant	Exon 2 of 5	6	NM_002122.5	ENSP00000339398.5		P01909

Frequencies

GnomAD3 genomes

AF:

0.228

AC:

18563

AN:

81386

Hom.:

3838

Cov.:

show subpopulations

Gnomad AFR

AF:

0.190

Gnomad AMI

AF:

0.328

Gnomad AMR

AF:

0.196

Gnomad ASJ

AF:

0.292

Gnomad EAS

AF:

0.146

Gnomad SAS

AF:

0.203

Gnomad FIN

AF:

0.118

Gnomad MID

AF:

0.325

Gnomad NFE

AF:

0.276

Gnomad OTH

AF:

0.240

GnomAD2 exomes

AF:

0.493

AC:

92599

AN:

187738

AF XY:

0.494

show subpopulations

Gnomad AFR exome

AF:

0.415

Gnomad AMR exome

AF:

0.668

Gnomad ASJ exome

AF:

0.551

Gnomad EAS exome

AF:

0.449

Gnomad FIN exome

AF:

0.403

Gnomad NFE exome

AF:

0.495

Gnomad OTH exome

AF:

0.450

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.232

AC:

192749

AN:

831528

Hom.:

68797

Cov.:

AF XY:

0.247

AC XY:

104198

AN XY:

422096

show subpopulations

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

African (AFR)

AF:

0.178

AC:

3712

AN:

20892

American (AMR)

AF:

0.534

AC:

14571

AN:

27306

Ashkenazi Jewish (ASJ)

AF:

0.330

AC:

4917

AN:

14912

East Asian (EAS)

AF:

0.129

AC:

3337

AN:

25792

South Asian (SAS)

AF:

0.358

AC:

20903

AN:

58394

European-Finnish (FIN)

AF:

0.197

AC:

7571

AN:

38386

Middle Eastern (MID)

AF:

0.387

AC:

1327

AN:

3432

European-Non Finnish (NFE)

AF:

0.213

AC:

129335

AN:

607798

Other (OTH)

AF:

0.204

AC:

7076

AN:

34616

⚠️ 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: 0.284

Heterozygous variant carriers

5136

10272

15408

20544

25680

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.228

AC:

18572

AN:

81452

Hom.:

3842

Cov.:

AF XY:

0.225

AC XY:

8955

AN XY:

39856

show subpopulations

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

African (AFR)

AF:

0.190

AC:

4363

AN:

22966

American (AMR)

AF:

0.197

AC:

1272

AN:

6472

Ashkenazi Jewish (ASJ)

AF:

0.292

AC:

523

AN:

1794

East Asian (EAS)

AF:

0.146

AC:

356

AN:

2446

South Asian (SAS)

AF:

0.202

AC:

536

AN:

2648

European-Finnish (FIN)

AF:

0.118

AC:

682

AN:

5762

Middle Eastern (MID)

AF:

0.333

AC:

AN:

114

European-Non Finnish (NFE)

AF:

0.276

AC:

10368

AN:

37620

Other (OTH)

AF:

0.235

AC:

256

AN:

1088

⚠️ 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: 0.298

Heterozygous variant carriers

780

1560

2340

3120

3900

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.580

Hom.:

67706

ESP6500AA

AF:

0.388

AC:

1711

ESP6500EA

AF:

0.441

AC:

3781

ExAC

AF:

0.555

AC:

67214

Asia WGS

AF:

0.469

AC:

1583

AN:

3376

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Jul 15, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 25349203) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.37

CADD

Benign

5.3

(source)

DANN

Benign

0.15

DEOGEN2

Benign

0.0032

.;.;T;.

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.0013

LIST_S2

Benign

0.34

.;.;T;T

MetaRNN

Benign

0.000011

T;T;T;T

MetaSVM

Benign

-1.1

PhyloP100

0.91

PrimateAI

Benign

0.41

PROVEAN

Benign

3.1

N;N;N;N

REVEL

Uncertain

0.29

Sift

Benign

1.0

T;T;T;T

Sift4G

Benign

1.0

T;T;T;T

Vest4

0.040

MPC

1.4

ClinPred

0.000028

GERP RS

3.0

gMVP

0.60

Mutation Taster

=99/1

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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6-32641349-T-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over