rs1048381

Variant names:

• chr6-32642668-G-A
• rs1048381
• NM_002122.5:c.672G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_002122.5(HLA-DQA1):​c.672G>A​(p.Gly224Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0202 in 1,220,146 control chromosomes in the GnomAD database, including 4,156 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0071 (4 hom., cov: 16)
  • Exomes 𝑓: 0.021 (4152 hom.)
• Consequence: HLA-DQA1 NM_002122.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.610
• Publications: 22 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP7: Synonymous conserved (PhyloP=-0.61 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.162 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-DQA1	NM_002122.5	c.672G>A	p.Gly224Gly	synonymous_variant	Exon 4 of 5	ENST00000343139.11	NP_002113.2
HLA-DQA1	XM_006715079.5	c.613+415G>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.672G>A	p.Gly224Gly	synonymous_variant	Exon 4 of 5	6	NM_002122.5	ENSP00000339398.5

Frequencies

GnomAD3 genomes AF: 0.00713 AC: 748 AN: 104924 Hom.: 4 Cov.: 16

Gnomad AFR AF: 0.0128

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00777

Gnomad ASJ AF: 0.00125

Gnomad EAS AF: 0.00982

Gnomad SAS AF: 0.00569

Gnomad FIN AF: 0.0136

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00310

Gnomad OTH AF: 0.00853

GnomAD2 exomes AF: 0.130 AC: 29319 AN: 225234 AF XY: 0.126

Gnomad AFR exome AF: 0.119

Gnomad AMR exome AF: 0.237

Gnomad ASJ exome AF: 0.0531

Gnomad EAS exome AF: 0.123

Gnomad FIN exome AF: 0.158

Gnomad NFE exome AF: 0.105

Gnomad OTH exome AF: 0.0965

GnomAD4 exome AF: 0.0214 AC: 23906 AN: 1115114 Hom.: 4152 Cov.: 32 AF XY: 0.0217 AC XY: 12148 AN XY: 560146

African (AFR) AF: 0.0380 AC: 991 AN: 26068

American (AMR) AF: 0.165 AC: 6008 AN: 36398

Ashkenazi Jewish (ASJ) AF: 0.0148 AC: 311 AN: 21014

East Asian (EAS) AF: 0.0406 AC: 1206 AN: 29676

South Asian (SAS) AF: 0.0328 AC: 2426 AN: 74038

European-Finnish (FIN) AF: 0.0421 AC: 1757 AN: 41770

Middle Eastern (MID) AF: 0.00854 AC: 33 AN: 3862

European-Non Finnish (NFE) AF: 0.0123 AC: 10244 AN: 835698

Other (OTH) AF: 0.0200 AC: 930 AN: 46590

GnomAD4 genome AF: 0.00713 AC: 749 AN: 105032 Hom.: 4 Cov.: 16 AF XY: 0.00742 AC XY: 377 AN XY: 50790

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

African (AFR) AF: 0.0127 AC: 368 AN: 28970

American (AMR) AF: 0.00788 AC: 69 AN: 8758

Ashkenazi Jewish (ASJ) AF: 0.00125 AC: 3 AN: 2402

East Asian (EAS) AF: 0.00984 AC: 29 AN: 2946

South Asian (SAS) AF: 0.00570 AC: 20 AN: 3510

European-Finnish (FIN) AF: 0.0136 AC: 96 AN: 7060

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 168

European-Non Finnish (NFE) AF: 0.00310 AC: 152 AN: 49046

Other (OTH) AF: 0.00843 AC: 12 AN: 1424

⚠️ 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: 0.123 Hom.: 519

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	1.5
DANN	Benign	0.33
PhyloP100		-0.61
Mutation Taster		=100/0	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: rs1048381; hg19: chr6-32610445; COSMIC: COSV58239552;