Genetic Variant HLA-DQA1:c.82+1404G>C (chr6-32638944-G-C) – ACMG Classification: Benign (-10 pts)

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.82+1404G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0010 ( 11 hom., cov: 18)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

HLA-DQA1
NM_002122.5 intron

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.99

Publications

4 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 (BayesDel_noAF=-0.93).

BP6

Variant 6-32638944-G-C is Benign according to our data. Variant chr6-32638944-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 2656468.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
HLA-DQA1	NM_002122.5 link	c.82+1404G>C	intron_variant	Intron 1 of 4	ENST00000343139.11	NP_002113.2	P01909A0A173ADG5Q8MH44
HLA-DQA1-AS1	XR_007059544.1 link	n.1219C>G	non_coding_transcript_exon_variant	Exon 2 of 2
HLA-DQA1	XM_006715079.5 link	c.82+1404G>C	intron_variant	Intron 1 of 3		XP_006715142.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLA-DQA1	ENST00000343139.11 link	c.82+1404G>C		intron_variant	Intron 1 of 4	6	NM_002122.5	ENSP00000339398.5		P01909

Frequencies

GnomAD3 genomes

AF:

0.00102

AC:

115

AN:

112676

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000869

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000577

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000249

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00154

Gnomad OTH

AF:

0.000673

GnomAD2 exomes

AF:

0.0000317

AC:

AN:

94508

AF XY:

0.0000385

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000562

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000213

AC:

AN:

234322

Hom.:

Cov.:

AF XY:

0.0000149

AC XY:

AN XY:

134518

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

6454

American (AMR)

AF:

0.00

AC:

AN:

19166

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

8380

East Asian (EAS)

AF:

0.00

AC:

AN:

7302

South Asian (SAS)

AF:

0.00

AC:

AN:

45586

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9880

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2014

European-Non Finnish (NFE)

AF:

0.0000321

AC:

AN:

124486

Other (OTH)

AF:

0.0000905

AC:

AN:

11054

⚠️ 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: 0.265

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00102

AC:

115

AN:

112794

Hom.:

Cov.:

AF XY:

0.00100

AC XY:

AN XY:

54854

show subpopulations

African (AFR)

AF:

0.000866

AC:

AN:

30026

American (AMR)

AF:

0.000577

AC:

AN:

10398

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2634

East Asian (EAS)

AF:

0.00

AC:

AN:

4126

South Asian (SAS)

AF:

0.00

AC:

AN:

3384

European-Finnish (FIN)

AF:

0.000249

AC:

AN:

8024

Middle Eastern (MID)

AF:

0.00

AC:

AN:

172

European-Non Finnish (NFE)

AF:

0.00154

AC:

AN:

51802

Other (OTH)

AF:

0.000664

AC:

AN:

1506

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Dec 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

HLA-DQA1: BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

0.51

(source)

DANN

Benign

0.39

PhyloP100

-2.0

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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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6-32638944-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over