6-32641435-C-T

Position:

• chr6-32641435-C-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.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. 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 0.033 (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

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=0.036417246).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0326 (2342/71920) while in subpopulation NFE AF= 0.0391 (1260/32240). AF 95% confidence interval is 0.0373. There are 199 homozygotes in gnomad4. There are 1108 alleles in male gnomad4 subpopulation. Median coverage is 13. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 199 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HLA-DQA1	NM_002122.5	c.208C>T	p.Arg70Trp	missense_variant	2/5	ENST00000343139.11	NP_002113.2
HLA-DQA1	XM_006715079.5	c.208C>T	p.Arg70Trp	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.208C>T	p.Arg70Trp	missense_variant	2/5	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

GnomAD3 exomes AF: 0.167 AC: 27932 AN: 167538 Hom.: 8249 AF XY: 0.166 AC XY: 15247 AN XY: 91660

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 SAS exome AF: 0.120

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

Gnomad4 AFR exome AF: 0.0259

Gnomad4 AMR exome AF: 0.144

Gnomad4 ASJ exome AF: 0.0499

Gnomad4 EAS exome AF: 0.0304

Gnomad4 SAS exome AF: 0.0584

Gnomad4 FIN exome AF: 0.0380

Gnomad4 NFE exome AF: 0.0184

Gnomad4 OTH exome AF: 0.0238

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

Gnomad4 AFR AF: 0.0301

Gnomad4 AMR AF: 0.0291

Gnomad4 ASJ AF: 0.0446

Gnomad4 EAS AF: 0.0172

Gnomad4 SAS AF: 0.0242

Gnomad4 FIN AF: 0.0148

Gnomad4 NFE AF: 0.0391

Gnomad4 OTH AF: 0.0300

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
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs1142326; hg19: chr6-32609212; COSMIC: COSV58237094; COSMIC: COSV58237094;