6-32637511-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.53T>C(p.Met18Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00135 in 1,169,610 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00028 ( 1 hom., cov: 15)

Exomes 𝑓: 0.0015 ( 20 hom. )

Consequence

HLA-DQA1
NM_002122.5 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.01

Publications

7 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=0.0029515028).

BP6

Variant 6-32637511-T-C is Benign according to our data. Variant chr6-32637511-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 3341556.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAdExome4 at 20 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-DQA1	NM_002122.5 link	c.53T>C	p.Met18Thr	missense_variant	Exon 1 of 5	ENST00000343139.11	NP_002113.2	P01909A0A173ADG5Q8MH44
HLA-DQA1	XM_006715079.5 link	c.53T>C	p.Met18Thr	missense_variant	Exon 1 of 4		XP_006715142.1
HLA-DQA1-AS1	XR_007059544.1 link	n.2652A>G		non_coding_transcript_exon_variant	Exon 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLA-DQA1	ENST00000343139.11 link	c.53T>C	p.Met18Thr	missense_variant	Exon 1 of 5	6	NM_002122.5	ENSP00000339398.5		P01909

Frequencies

GnomAD3 genomes

AF:

0.000278

AC:

AN:

100650

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00160

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00330

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00122

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000179

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0187

AC:

4530

AN:

241770

AF XY:

0.0180

show subpopulations

Gnomad AFR exome

AF:

0.00180

Gnomad AMR exome

AF:

0.00486

Gnomad ASJ exome

AF:

0.00317

Gnomad EAS exome

AF:

0.124

Gnomad FIN exome

AF:

0.0433

Gnomad NFE exome

AF:

0.00918

Gnomad OTH exome

AF:

0.0111

GnomAD4 exome

AF:

0.00145

AC:

1554

AN:

1068858

Hom.:

Cov.:

AF XY:

0.00155

AC XY:

834

AN XY:

538524

show subpopulations

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

African (AFR)

AF:

0.000279

AC:

AN:

28664

American (AMR)

AF:

0.00156

AC:

AN:

35348

Ashkenazi Jewish (ASJ)

AF:

0.000835

AC:

AN:

19152

East Asian (EAS)

AF:

0.00771

AC:

221

AN:

28678

South Asian (SAS)

AF:

0.00162

AC:

117

AN:

72172

European-Finnish (FIN)

AF:

0.00361

AC:

163

AN:

45168

Middle Eastern (MID)

AF:

0.000272

AC:

AN:

3674

European-Non Finnish (NFE)

AF:

0.00117

AC:

923

AN:

791024

Other (OTH)

AF:

0.00111

AC:

AN:

44978

⚠️ 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: 0.381

Heterozygous variant carriers

149

224

298

373

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000278

AC:

AN:

100752

Hom.:

Cov.:

AF XY:

0.000285

AC XY:

AN XY:

49154

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

29874

American (AMR)

AF:

0.00

AC:

AN:

8432

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2062

East Asian (EAS)

AF:

0.00331

AC:

AN:

3018

South Asian (SAS)

AF:

0.00

AC:

AN:

3190

European-Finnish (FIN)

AF:

0.00122

AC:

AN:

7352

Middle Eastern (MID)

AF:

0.00

AC:

AN:

152

European-Non Finnish (NFE)

AF:

0.000179

AC:

AN:

44718

Other (OTH)

AF:

0.00

AC:

AN:

1330

⚠️ 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: 0.269

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00777

Hom.:

TwinsUK

AF:

0.0119

AC:

ALSPAC

AF:

0.0127

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00895

AC:

ExAC

AF:

0.0204

AC:

2482

Asia WGS

AF:

0.0430

AC:

151

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

HLA-DQA1: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

DANN

Benign

0.55

DEOGEN2

Benign

0.033

.;.;.;T;.

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.81

FATHMM_MKL

Benign

0.018

LIST_S2

Benign

0.65

T;.;.;T;T

MetaRNN

Benign

0.0030

T;T;T;T;T

MetaSVM

Benign

-1.1

PhyloP100

1.0

PrimateAI

Benign

0.37

PROVEAN

Pathogenic

-5.5

D;N;N;N;N

REVEL

Benign

0.23

Sift

Benign

0.053

.;T;T;D;T

Sift4G

Pathogenic

0.0

D;D;D;D;D

Vest4

0.092, 0.14, 0.10

MPC

0.96

ClinPred

0.0093

GERP RS

3.0

PromoterAI

0.11

Neutral

(source)

gMVP

0.50

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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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6-32637511-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