rs1048052

Positions:

• chr6-32641453-A-C
• chr6-32641453-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_002122.5(HLA-DQA1):​c.226A>C​(p.Lys76Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/17 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 0.021 (101 hom., cov: 13)
  • Exomes 𝑓: 0.010 (3727 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-DQA1 NM_002122.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.27

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=0.015239656).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0214 (1673/78028) while in subpopulation NFE AF= 0.025 (872/34812). AF 95% confidence interval is 0.0237. There are 101 homozygotes in gnomad4. There are 770 alleles in male gnomad4 subpopulation. Median coverage is 13. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 101 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HLA-DQA1	NM_002122.5	c.226A>C	p.Lys76Gln	missense_variant	2/5	ENST00000343139.11	NP_002113.2
HLA-DQA1	XM_006715079.5	c.226A>C	p.Lys76Gln	missense_variant	2/4		XP_006715142.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HLA-DQA1	ENST00000343139.11	c.226A>C	p.Lys76Gln	missense_variant	2/5	6	NM_002122.5	ENSP00000339398.5

Frequencies

GnomAD3 genomes AF: 0.0215 AC: 1675 AN: 77942 Hom.: 101 Cov.: 13

Gnomad AFR AF: 0.0207

Gnomad AMI AF: 0.0199

Gnomad AMR AF: 0.0196

Gnomad ASJ AF: 0.0246

Gnomad EAS AF: 0.0118

Gnomad SAS AF: 0.0145

Gnomad FIN AF: 0.0114

Gnomad MID AF: 0.0339

Gnomad NFE AF: 0.0251

Gnomad OTH AF: 0.0254

GnomAD3 exomes AF: 0.128 AC: 20729 AN: 161970 Hom.: 5961 AF XY: 0.127 AC XY: 11304 AN XY: 88732

Gnomad AFR exome AF: 0.138

Gnomad AMR exome AF: 0.186

Gnomad ASJ exome AF: 0.0975

Gnomad EAS exome AF: 0.118

Gnomad SAS exome AF: 0.0880

Gnomad FIN exome AF: 0.114

Gnomad NFE exome AF: 0.134

Gnomad OTH exome AF: 0.0945

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0101 AC: 9206 AN: 915728 Hom.: 3727 Cov.: 26 AF XY: 0.0118 AC XY: 5408 AN XY: 458594

Gnomad4 AFR exome AF: 0.00981

Gnomad4 AMR exome AF: 0.0385

Gnomad4 ASJ exome AF: 0.0158

Gnomad4 EAS exome AF: 0.0115

Gnomad4 SAS exome AF: 0.0237

Gnomad4 FIN exome AF: 0.0161

Gnomad4 NFE exome AF: 0.00748

Gnomad4 OTH exome AF: 0.00965

GnomAD4 genome AF: 0.0214 AC: 1673 AN: 78028 Hom.: 101 Cov.: 13 AF XY: 0.0203 AC XY: 770 AN XY: 37948

Gnomad4 AFR AF: 0.0206

Gnomad4 AMR AF: 0.0194

Gnomad4 ASJ AF: 0.0246

Gnomad4 EAS AF: 0.0114

Gnomad4 SAS AF: 0.0141

Gnomad4 FIN AF: 0.0114

Gnomad4 NFE AF: 0.0250

Gnomad4 OTH AF: 0.0258

Alfa AF: 0.104 Hom.: 327

ExAC AF: 0.254 AC: 28450

Asia WGS AF: 0.252 AC: 863 AN: 3428

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.0050
DANN	Benign	0.084
DEOGEN2	Benign	0.0020	.;.;T;.
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.80	.;.;T;T
MetaRNN	Benign	0.015	T;T;T;T
MetaSVM	Benign	-0.96	T
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.63	N;N;N;N
REVEL	Benign	0.023
Sift	Benign	0.79	T;T;T;T
Sift4G	Benign	0.62	T;T;T;T
Vest4		0.043
MPC		0.89
ClinPred		0.0019	T
GERP RS		-8.0
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1048052; hg19: chr6-32609230; COSMIC: COSV58238941; COSMIC: COSV58238941;