6-32641435-C-T

Variant names:

• chr6-32641435-C-T
• rs1142326
• NM_002122.5:c.208C>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.208C>T​(p.Arg70Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/18 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 0.033 (199 hom., cov: 13)
  • Exomes 𝑓: 0.026 (8949 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-DQA1 NM_002122.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.255
• Publications: 16 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=0.036417246).
• BS2: High Homozygotes in GnomAd4 at 199 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-DQA1	NM_002122.5	c.208C>T	p.Arg70Trp	missense_variant	Exon 2 of 5	ENST00000343139.11	NP_002113.2
HLA-DQA1	XM_006715079.5	c.208C>T	p.Arg70Trp	missense_variant	Exon 2 of 4		XP_006715142.1
HLA-DQA1-AS1	XR_007059544.1	n.-125G>A		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLA-DQA1	ENST00000343139.11	c.208C>T	p.Arg70Trp	missense_variant	Exon 2 of 5	6	NM_002122.5	ENSP00000339398.5

Frequencies

GnomAD3 genomes AF: 0.0326 AC: 2341 AN: 71842 Hom.: 199 Cov.: 13

Gnomad AFR AF: 0.0301

Gnomad AMI AF: 0.0242

Gnomad AMR AF: 0.0293

Gnomad ASJ AF: 0.0446

Gnomad EAS AF: 0.0176

Gnomad SAS AF: 0.0243

Gnomad FIN AF: 0.0148

Gnomad MID AF: 0.0745

Gnomad NFE AF: 0.0391

Gnomad OTH AF: 0.0296

GnomAD2 exomes AF: 0.167 AC: 27932 AN: 167538 AF XY: 0.166

Gnomad AFR exome AF: 0.168

Gnomad AMR exome AF: 0.237

Gnomad ASJ exome AF: 0.144

Gnomad EAS exome AF: 0.146

Gnomad FIN exome AF: 0.157

Gnomad NFE exome AF: 0.174

Gnomad OTH exome AF: 0.122

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0264 AC: 23824 AN: 902950 Hom.: 8949 Cov.: 27 AF XY: 0.0310 AC XY: 14048 AN XY: 453824

African (AFR) AF: 0.0259 AC: 607 AN: 23466

American (AMR) AF: 0.144 AC: 3033 AN: 21018

Ashkenazi Jewish (ASJ) AF: 0.0499 AC: 766 AN: 15348

East Asian (EAS) AF: 0.0304 AC: 784 AN: 25768

South Asian (SAS) AF: 0.0584 AC: 3680 AN: 62978

European-Finnish (FIN) AF: 0.0380 AC: 1383 AN: 36352

Middle Eastern (MID) AF: 0.0779 AC: 242 AN: 3106

European-Non Finnish (NFE) AF: 0.0184 AC: 12424 AN: 676882

Other (OTH) AF: 0.0238 AC: 905 AN: 38032

GnomAD4 genome AF: 0.0326 AC: 2342 AN: 71920 Hom.: 199 Cov.: 13 AF XY: 0.0316 AC XY: 1108 AN XY: 35066

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

African (AFR) AF: 0.0301 AC: 620 AN: 20594

American (AMR) AF: 0.0291 AC: 170 AN: 5840

Ashkenazi Jewish (ASJ) AF: 0.0446 AC: 67 AN: 1502

East Asian (EAS) AF: 0.0172 AC: 42 AN: 2436

South Asian (SAS) AF: 0.0242 AC: 56 AN: 2310

European-Finnish (FIN) AF: 0.0148 AC: 82 AN: 5552

Middle Eastern (MID) AF: 0.0761 AC: 7 AN: 92

European-Non Finnish (NFE) AF: 0.0391 AC: 1260 AN: 32240

Other (OTH) AF: 0.0300 AC: 27 AN: 900

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.106 Hom.: 319

ExAC AF: 0.254 AC: 29021

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	13
DANN	Benign	0.97
DEOGEN2	Benign	0.020	.;.;T;.
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.038	N
LIST_S2	Benign	0.81	.;.;T;T
MetaRNN	Benign	0.036	T;T;T;T
MetaSVM	Benign	-0.93	T
PhyloP100		-0.26
PrimateAI	Benign	0.21	T
PROVEAN	Pathogenic	-5.6	D;D;D;D
REVEL	Benign	0.055
Sift	Uncertain	0.022	D;D;D;D
Sift4G	Uncertain	0.052	T;T;T;T
Vest4		0.10
MPC		0.88
ClinPred		0.053	T
GERP RS		-0.47
gMVP		0.55
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1142326; hg19: chr6-32609212; COSMIC: COSV58237094; COSMIC: COSV58237094;