rs9272699

chr6-32641452-C-Achr6-32641452-C-G

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.225C>A(p.Ser75Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0219 in 78,214 control chromosomes in the GnomAD database, including 107 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 0.022 (107 hom., cov: 13)
  • Exomes 𝑓: 0.011 (3978 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-DQA1 NM_002122.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.21

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002570182).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0219 (1710/78214) while in subpopulation NFE AF= 0.0255 (891/34994). AF 95% confidence interval is 0.0241. There are 107 homozygotes in gnomad4. There are 787 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 107 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HLA-DQA1	NM_002122.5	c.225C>A	p.Ser75Arg	missense_variant	2/5	ENST00000343139.11
HLA-DQA1	XM_006715079.5	c.225C>A	p.Ser75Arg	missense_variant	2/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HLA-DQA1	ENST00000343139.11	c.225C>A	p.Ser75Arg	missense_variant	2/5		NM_002122.5	P1

Frequencies

GnomAD3 genomes AF: 0.0219 AC: 1712 AN: 78132 Hom.: 107 Cov.: 13

Gnomad AFR AF: 0.0210

Gnomad AMI AF: 0.0219

Gnomad AMR AF: 0.0202

Gnomad ASJ AF: 0.0245

Gnomad EAS AF: 0.0123

Gnomad SAS AF: 0.0147

Gnomad FIN AF: 0.0118

Gnomad MID AF: 0.0431

Gnomad NFE AF: 0.0255

Gnomad OTH AF: 0.0262

GnomAD3 exomes AF: 0.130 AC: 21202 AN: 163220 Hom.: 6050 AF XY: 0.129 AC XY: 11555 AN XY: 89410

Gnomad AFR exome AF: 0.140

Gnomad AMR exome AF: 0.186

Gnomad ASJ exome AF: 0.101

Gnomad EAS exome AF: 0.119

Gnomad SAS exome AF: 0.0894

Gnomad FIN exome AF: 0.117

Gnomad NFE exome AF: 0.137

Gnomad OTH exome AF: 0.0956

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0108 AC: 9846 AN: 915470 Hom.: 3978 Cov.: 26 AF XY: 0.0126 AC XY: 5765 AN XY: 458564

Gnomad4 AFR exome AF: 0.0106

Gnomad4 AMR exome AF: 0.0408

Gnomad4 ASJ exome AF: 0.0171

Gnomad4 EAS exome AF: 0.0124

Gnomad4 SAS exome AF: 0.0252

Gnomad4 FIN exome AF: 0.0172

Gnomad4 NFE exome AF: 0.00801

Gnomad4 OTH exome AF: 0.0105

GnomAD4 genome AF: 0.0219 AC: 1710 AN: 78214 Hom.: 107 Cov.: 13 AF XY: 0.0207 AC XY: 787 AN XY: 38044

Gnomad4 AFR AF: 0.0209

Gnomad4 AMR AF: 0.0201

Gnomad4 ASJ AF: 0.0245

Gnomad4 EAS AF: 0.0119

Gnomad4 SAS AF: 0.0143

Gnomad4 FIN AF: 0.0118

Gnomad4 NFE AF: 0.0255

Gnomad4 OTH AF: 0.0266

Alfa AF: 0.104 Hom.: 327

ExAC AF: 0.253 AC: 28495

Asia WGS AF: 0.251 AC: 863 AN: 3442

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	7.9
Dann	Benign	0.91
Eigen	Benign	-0.97
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.046	N
MetaRNN	Benign	0.0026	T;T;T;T
MetaSVM	Benign	-0.92	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-2.8	D;D;D;D
REVEL	Benign	0.028
Sift	Benign	0.19	T;T;T;T
Sift4G	Benign	0.10	T;T;T;T
Vest4		0.12
MutPred		0.34		Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);
MPC		0.96
ClinPred		0.0059	T
GERP RS		-0.34
gMVP		0.41

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: rs9272699; hg19: chr6-32609229; COSMIC: COSV58238932; COSMIC: COSV58238932;