rs1048052

Variant names:

• chr6-32641453-A-C
• rs1048052
• NM_002122.5:c.226A>C

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong 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. 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 0.021 (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
• Publications: 12 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]

HLA-DQA1-AS1 (HGNC:56667): (HLA-DQA1 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015239656).
• BS2: High Homozygotes in GnomAd4 at 101 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-DQA1	NM_002122.5	c.226A>C	p.Lys76Gln	missense_variant	Exon 2 of 5	ENST00000343139.11	NP_002113.2
HLA-DQA1	XM_006715079.5	c.226A>C	p.Lys76Gln	missense_variant	Exon 2 of 4		XP_006715142.1
HLA-DQA1-AS1	XR_007059544.1	n.-143T>G		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLA-DQA1	ENST00000343139.11	c.226A>C	p.Lys76Gln	missense_variant	Exon 2 of 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

GnomAD2 exomes AF: 0.128 AC: 20729 AN: 161970 AF XY: 0.127

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 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

African (AFR) AF: 0.00981 AC: 233 AN: 23758

American (AMR) AF: 0.0385 AC: 733 AN: 19044

Ashkenazi Jewish (ASJ) AF: 0.0158 AC: 238 AN: 15042

East Asian (EAS) AF: 0.0115 AC: 295 AN: 25668

South Asian (SAS) AF: 0.0237 AC: 1468 AN: 61922

European-Finnish (FIN) AF: 0.0161 AC: 590 AN: 36690

Middle Eastern (MID) AF: 0.0321 AC: 101 AN: 3150

European-Non Finnish (NFE) AF: 0.00748 AC: 5177 AN: 691992

Other (OTH) AF: 0.00965 AC: 371 AN: 38462

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

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

African (AFR) AF: 0.0206 AC: 467 AN: 22636

American (AMR) AF: 0.0194 AC: 123 AN: 6332

Ashkenazi Jewish (ASJ) AF: 0.0246 AC: 39 AN: 1586

East Asian (EAS) AF: 0.0114 AC: 29 AN: 2534

South Asian (SAS) AF: 0.0141 AC: 36 AN: 2556

European-Finnish (FIN) AF: 0.0114 AC: 68 AN: 5990

Middle Eastern (MID) AF: 0.0357 AC: 4 AN: 112

European-Non Finnish (NFE) AF: 0.0250 AC: 872 AN: 34812

Other (OTH) AF: 0.0258 AC: 25 AN: 968

⚠️ 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: 0.104 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
AlphaMissense	Benign	0.091
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
PhyloP100		-2.3
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
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1048052; hg19: chr6-32609230; COSMIC: COSV58238941; COSMIC: COSV58238941;