NM_002122.5:c.250G>T

Variant names:

• chr6-32641477-G-T
• rs1142331
• NM_002122.5:c.250G>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.250G>T​(p.Gly84Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/19 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 0.012 (36 hom., cov: 13)
  • Exomes 𝑓: 0.0052 (2280 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-DQA1 NM_002122.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.47
• Publications: 11 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=0.011225879).
• BS2: High Homozygotes in GnomAd4 at 36 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002122.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLA-DQA1	NM_002122.5	MANE Select	c.250G>T	p.Gly84Cys	missense	Exon 2 of 5	NP_002113.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLA-DQA1	ENST00000343139.11	TSL:6 MANE Select	c.250G>T	p.Gly84Cys	missense	Exon 2 of 5	ENSP00000339398.5
	HLA-DQA1	ENST00000374949.2	TSL:6	c.250G>T	p.Gly84Cys	missense	Exon 2 of 4	ENSP00000364087.2
	HLA-DQA1	ENST00000395363.5	TSL:6	c.250G>T	p.Gly84Cys	missense	Exon 2 of 5	ENSP00000378767.1

Frequencies

GnomAD3 genomes AF: 0.0124 AC: 1009 AN: 81226 Hom.: 35 Cov.: 13

Gnomad AFR AF: 0.0127

Gnomad AMI AF: 0.00800

Gnomad AMR AF: 0.0139

Gnomad ASJ AF: 0.0147

Gnomad EAS AF: 0.00714

Gnomad SAS AF: 0.00664

Gnomad FIN AF: 0.00720

Gnomad MID AF: 0.00794

Gnomad NFE AF: 0.0135

Gnomad OTH AF: 0.0125

GnomAD2 exomes AF: 0.0753 AC: 10718 AN: 142246 AF XY: 0.0717

Gnomad AFR exome AF: 0.0967

Gnomad AMR exome AF: 0.109

Gnomad ASJ exome AF: 0.0561

Gnomad EAS exome AF: 0.0775

Gnomad FIN exome AF: 0.0628

Gnomad NFE exome AF: 0.0803

Gnomad OTH exome AF: 0.0511

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00523 AC: 4848 AN: 926826 Hom.: 2280 Cov.: 24 AF XY: 0.00605 AC XY: 2809 AN XY: 464428

African (AFR) AF: 0.00461 AC: 111 AN: 24092

American (AMR) AF: 0.0223 AC: 429 AN: 19264

Ashkenazi Jewish (ASJ) AF: 0.00770 AC: 118 AN: 15316

East Asian (EAS) AF: 0.00487 AC: 127 AN: 26088

South Asian (SAS) AF: 0.0129 AC: 806 AN: 62478

European-Finnish (FIN) AF: 0.00645 AC: 244 AN: 37806

Middle Eastern (MID) AF: 0.00961 AC: 31 AN: 3226

European-Non Finnish (NFE) AF: 0.00394 AC: 2753 AN: 699540

Other (OTH) AF: 0.00587 AC: 229 AN: 39016

GnomAD4 genome AF: 0.0124 AC: 1010 AN: 81322 Hom.: 36 Cov.: 13 AF XY: 0.0116 AC XY: 457 AN XY: 39446

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

African (AFR) AF: 0.0128 AC: 297 AN: 23216

American (AMR) AF: 0.0138 AC: 92 AN: 6690

Ashkenazi Jewish (ASJ) AF: 0.0147 AC: 25 AN: 1698

East Asian (EAS) AF: 0.00677 AC: 17 AN: 2510

South Asian (SAS) AF: 0.00663 AC: 18 AN: 2716

European-Finnish (FIN) AF: 0.00720 AC: 42 AN: 5832

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 118

European-Non Finnish (NFE) AF: 0.0135 AC: 501 AN: 36980

Other (OTH) AF: 0.0132 AC: 14 AN: 1062

⚠️ 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: 0.182 Hom.: 747

ExAC AF: 0.306 AC: 33558

Asia WGS AF: 0.443 AC: 1523 AN: 3436

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	18
DANN	Benign	0.94
DEOGEN2	Benign	0.068	T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.49	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.88	T
PhyloP100		2.5
PrimateAI	Benign	0.36	T
PROVEAN	Pathogenic	-6.8	D
REVEL	Benign	0.20
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Vest4		0.23
MPC		1.7
ClinPred		0.057	T
GERP RS		2.1
gMVP		0.58
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: rs1142331; hg19: chr6-32609254; COSMIC: COSV58237257; COSMIC: COSV58237257;