rs1129740

Variant names:

• chr6-32641328-G-A
• rs1129740
• NM_002122.5:c.101G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_002122.5(HLA-DQA1):​c.101G>A​(p.Cys34Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.26 (4413 hom., cov: 16)
  • Exomes 𝑓: 0.29 (93358 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-DQA1 NM_002122.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.525
• Publications: 57 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.0995187E-5).
• BP6: Variant 6-32641328-G-A is Benign according to our data. Variant chr6-32641328-G-A is described in ClinVar as Benign. ClinVar VariationId is 1258533.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 4413 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLA-DQA1	NM_002122.5	MANE Select	c.101G>A	p.Cys34Tyr	missense	Exon 2 of 5	NP_002113.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLA-DQA1	ENST00000343139.11	TSL:6 MANE Select	c.101G>A	p.Cys34Tyr	missense	Exon 2 of 5	ENSP00000339398.5	P01909
	HLA-DQA1	ENST00000374949.2	TSL:6	c.101G>A	p.Cys34Tyr	missense	Exon 2 of 4	ENSP00000364087.2	P01909
	HLA-DQA1	ENST00000395363.5	TSL:6	c.101G>A	p.Cys34Tyr	missense	Exon 2 of 5	ENSP00000378767.1	P01909

Frequencies

GnomAD3 genomes AF: 0.256 AC: 20344 AN: 79544 Hom.: 4407 Cov.: 16

Gnomad AFR AF: 0.214

Gnomad AMI AF: 0.381

Gnomad AMR AF: 0.228

Gnomad ASJ AF: 0.321

Gnomad EAS AF: 0.186

Gnomad SAS AF: 0.228

Gnomad FIN AF: 0.137

Gnomad MID AF: 0.383

Gnomad NFE AF: 0.305

Gnomad OTH AF: 0.256

GnomAD2 exomes AF: 0.495 AC: 94628 AN: 191328 AF XY: 0.496

Gnomad AFR exome AF: 0.417

Gnomad AMR exome AF: 0.662

Gnomad ASJ exome AF: 0.556

Gnomad EAS exome AF: 0.450

Gnomad FIN exome AF: 0.403

Gnomad NFE exome AF: 0.496

Gnomad OTH exome AF: 0.458

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.292 AC: 266227 AN: 910226 Hom.: 93358 Cov.: 27 AF XY: 0.303 AC XY: 139266 AN XY: 460174

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

African (AFR) AF: 0.220 AC: 4916 AN: 22306

American (AMR) AF: 0.549 AC: 15611 AN: 28434

Ashkenazi Jewish (ASJ) AF: 0.362 AC: 5767 AN: 15938

East Asian (EAS) AF: 0.140 AC: 3622 AN: 25830

South Asian (SAS) AF: 0.386 AC: 24122 AN: 62516

European-Finnish (FIN) AF: 0.212 AC: 8038 AN: 37950

Middle Eastern (MID) AF: 0.421 AC: 1535 AN: 3648

European-Non Finnish (NFE) AF: 0.285 AC: 192998 AN: 676488

Other (OTH) AF: 0.259 AC: 9618 AN: 37116

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.256 AC: 20360 AN: 79622 Hom.: 4413 Cov.: 16 AF XY: 0.251 AC XY: 9728 AN XY: 38744

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

African (AFR) AF: 0.214 AC: 4841 AN: 22648

American (AMR) AF: 0.229 AC: 1407 AN: 6150

Ashkenazi Jewish (ASJ) AF: 0.321 AC: 558 AN: 1740

East Asian (EAS) AF: 0.187 AC: 430 AN: 2302

South Asian (SAS) AF: 0.228 AC: 607 AN: 2668

European-Finnish (FIN) AF: 0.137 AC: 749 AN: 5478

Middle Eastern (MID) AF: 0.395 AC: 45 AN: 114

European-Non Finnish (NFE) AF: 0.305 AC: 11243 AN: 36898

Other (OTH) AF: 0.252 AC: 271 AN: 1076

⚠️ 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: 0.583 Hom.: 44721

ESP6500AA AF: 0.424 AC: 1866

ESP6500EA AF: 0.465 AC: 3996

ExAC AF: 0.556 AC: 67297

Asia WGS AF: 0.469 AC: 1584 AN: 3374

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	0.075
DANN	Benign	0.23
DEOGEN2	Benign	0.0012	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0020	N
LIST_S2	Benign	0.70	T
MetaRNN	Benign	0.000021	T
MetaSVM	Benign	-0.96	T
PhyloP100		0.53
PrimateAI	Benign	0.39	T
PROVEAN	Benign	4.8	N
REVEL	Benign	0.28
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Vest4		0.060
MPC		1.4
ClinPred		0.0047	T
GERP RS		-0.28
gMVP		0.60
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1129740; hg19: chr6-32609105; COSMIC: COSV58237735; COSMIC: COSV58237735;