rs9272785

Variant names:

• chr6-32642624-G-A
• rs9272785
• NM_002122.5:c.628G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002122.5(HLA-DQA1):​c.628G>A​(p.Ala210Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.11 in 1,189,734 control chromosomes in the GnomAD database, including 26,215 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 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 0.088 (905 hom., cov: 17)
  • Exomes 𝑓: 0.11 (25310 hom.)
• Consequence: HLA-DQA1 NM_002122.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.35
• Publications: 45 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0037218034).
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.264 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-DQA1	NM_002122.5	c.628G>A	p.Ala210Thr	missense_variant	Exon 4 of 5	ENST00000343139.11	NP_002113.2
HLA-DQA1	XM_006715079.5	c.613+371G>A		intron_variant	Intron 3 of 3		XP_006715142.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLA-DQA1	ENST00000343139.11	c.628G>A	p.Ala210Thr	missense_variant	Exon 4 of 5	6	NM_002122.5	ENSP00000339398.5

Frequencies

GnomAD3 genomes AF: 0.0884 AC: 9302 AN: 105264 Hom.: 901 Cov.: 17

Gnomad AFR AF: 0.0502

Gnomad AMI AF: 0.116

Gnomad AMR AF: 0.119

Gnomad ASJ AF: 0.125

Gnomad EAS AF: 0.185

Gnomad SAS AF: 0.0482

Gnomad FIN AF: 0.0954

Gnomad MID AF: 0.0870

Gnomad NFE AF: 0.100

Gnomad OTH AF: 0.0795

GnomAD2 exomes AF: 0.184 AC: 44049 AN: 239932 AF XY: 0.174

Gnomad AFR exome AF: 0.101

Gnomad AMR exome AF: 0.282

Gnomad ASJ exome AF: 0.192

Gnomad EAS exome AF: 0.298

Gnomad FIN exome AF: 0.189

Gnomad NFE exome AF: 0.173

Gnomad OTH exome AF: 0.170

GnomAD4 exome AF: 0.112 AC: 121673 AN: 1084386 Hom.: 25310 Cov.: 32 AF XY: 0.111 AC XY: 60386 AN XY: 545494

African (AFR) AF: 0.0523 AC: 1445 AN: 27636

American (AMR) AF: 0.268 AC: 9952 AN: 37146

Ashkenazi Jewish (ASJ) AF: 0.140 AC: 2770 AN: 19764

East Asian (EAS) AF: 0.256 AC: 6739 AN: 26294

South Asian (SAS) AF: 0.0576 AC: 4306 AN: 74788

European-Finnish (FIN) AF: 0.115 AC: 4587 AN: 40052

Middle Eastern (MID) AF: 0.0673 AC: 243 AN: 3612

European-Non Finnish (NFE) AF: 0.107 AC: 86824 AN: 809870

Other (OTH) AF: 0.106 AC: 4807 AN: 45224

GnomAD4 genome AF: 0.0885 AC: 9320 AN: 105348 Hom.: 905 Cov.: 17 AF XY: 0.0890 AC XY: 4547 AN XY: 51110

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

African (AFR) AF: 0.0503 AC: 1508 AN: 29962

American (AMR) AF: 0.120 AC: 1041 AN: 8670

Ashkenazi Jewish (ASJ) AF: 0.125 AC: 298 AN: 2378

East Asian (EAS) AF: 0.186 AC: 563 AN: 3020

South Asian (SAS) AF: 0.0488 AC: 177 AN: 3630

European-Finnish (FIN) AF: 0.0954 AC: 675 AN: 7076

Middle Eastern (MID) AF: 0.0882 AC: 15 AN: 170

European-Non Finnish (NFE) AF: 0.100 AC: 4851 AN: 48340

Other (OTH) AF: 0.0793 AC: 112 AN: 1412

⚠️ 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.

Alfa AF: 0.163 Hom.: 836

ESP6500AA AF: 0.108 AC: 325

ESP6500EA AF: 0.178 AC: 965

ExAC AF: 0.182 AC: 21447

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.85	T
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.25
DANN	Benign	0.39
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.70	.;.;T
MetaRNN	Benign	0.0037	T;T;T
MetaSVM	Benign	-0.93	T
PhyloP100		-1.4
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.75	N;N;N
REVEL	Benign	0.011
Sift	Benign	0.51	T;T;T
Sift4G	Benign	1.0	T;T;T
Vest4		0.097
MPC		0.82
ClinPred		0.0051	T
GERP RS		-3.5
gMVP		0.18
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs9272785; hg19: chr6-32610401; COSMIC: COSV58237396;