rs7990

Positions:

• chr6-32642188-C-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002122.5(HLA-DQA1):​c.548C>A​(p.Ala183Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0464 in 1,321,916 control chromosomes in the GnomAD database, including 5,811 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/17 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 0.013 (17 hom., cov: 16)
  • Exomes 𝑓: 0.049 (5794 hom.)
• Consequence: HLA-DQA1 NM_002122.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.51

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0022338629).
• BA1: GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.147 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HLA-DQA1	NM_002122.5	c.548C>A	p.Ala183Asp	missense_variant	3/5	ENST00000343139.11	NP_002113.2
HLA-DQA1	XM_006715079.5	c.548C>A	p.Ala183Asp	missense_variant	3/4		XP_006715142.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HLA-DQA1	ENST00000343139.11	c.548C>A	p.Ala183Asp	missense_variant	3/5	6	NM_002122.5	ENSP00000339398.5

Frequencies

GnomAD3 genomes AF: 0.0125 AC: 1249 AN: 99782 Hom.: 17 Cov.: 16

Gnomad AFR AF: 0.0123

Gnomad AMI AF: 0.0238

Gnomad AMR AF: 0.00817

Gnomad ASJ AF: 0.00769

Gnomad EAS AF: 0.0384

Gnomad SAS AF: 0.00375

Gnomad FIN AF: 0.00764

Gnomad MID AF: 0.0118

Gnomad NFE AF: 0.0135

Gnomad OTH AF: 0.0100

GnomAD3 exomes AF: 0.0662 AC: 15811 AN: 238892 Hom.: 1096 AF XY: 0.0635 AC XY: 8291 AN XY: 130522

Gnomad AFR exome AF: 0.0722

Gnomad AMR exome AF: 0.0352

Gnomad ASJ exome AF: 0.0270

Gnomad EAS exome AF: 0.201

Gnomad SAS exome AF: 0.0164

Gnomad FIN exome AF: 0.0733

Gnomad NFE exome AF: 0.0705

Gnomad OTH exome AF: 0.0593

GnomAD4 exome AF: 0.0492 AC: 60075 AN: 1222044 Hom.: 5794 Cov.: 32 AF XY: 0.0478 AC XY: 29374 AN XY: 614234

Gnomad4 AFR exome AF: 0.0395

Gnomad4 AMR exome AF: 0.0321

Gnomad4 ASJ exome AF: 0.0202

Gnomad4 EAS exome AF: 0.151

Gnomad4 SAS exome AF: 0.0119

Gnomad4 FIN exome AF: 0.0386

Gnomad4 NFE exome AF: 0.0518

Gnomad4 OTH exome AF: 0.0449

GnomAD4 genome AF: 0.0125 AC: 1253 AN: 99872 Hom.: 17 Cov.: 16 AF XY: 0.0124 AC XY: 602 AN XY: 48658

Gnomad4 AFR AF: 0.0124

Gnomad4 AMR AF: 0.00828

Gnomad4 ASJ AF: 0.00769

Gnomad4 EAS AF: 0.0386

Gnomad4 SAS AF: 0.00375

Gnomad4 FIN AF: 0.00764

Gnomad4 NFE AF: 0.0135

Gnomad4 OTH AF: 0.00994

Alfa AF: 0.0569 Hom.: 81

ESP6500AA AF: 0.0775 AC: 234

ESP6500EA AF: 0.0843 AC: 456

ExAC AF: 0.0768 AC: 9000

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	6.3
DANN	Benign	0.49
DEOGEN2	Benign	0.011	.;.;T;.
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.35	.;.;T;T
MetaRNN	Benign	0.0022	T;T;T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-2.1	N;N;N;N
REVEL	Benign	0.049
Sift	Benign	0.52	T;T;T;T
Sift4G	Benign	0.54	T;T;T;T
Vest4		0.064
MPC		1.2
ClinPred		0.0043	T
GERP RS		-2.0
gMVP		0.40

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

LitVar

Other links and lift over

dbSNP: rs7990; hg19: chr6-32609965; COSMIC: COSV58238540; COSMIC: COSV58238540;