rs9272699

Variant names:

• chr6-32641452-C-A
• rs9272699
• NM_002122.5:c.225C>A

Your query was ambiguous. Multiple possible variants found:

• chr6-32641452-C-A
• chr6-32641452-C-G

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.225C>A​(p.Ser75Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/19 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 0.022 (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
• 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=0.002570182).
• BS2: High Homozygotes in GnomAd4 at 107 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.225C>A	p.Ser75Arg	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.225C>A	p.Ser75Arg	missense	Exon 2 of 5	ENSP00000339398.5
	HLA-DQA1	ENST00000374949.2	TSL:6	c.225C>A	p.Ser75Arg	missense	Exon 2 of 4	ENSP00000364087.2
	HLA-DQA1	ENST00000395363.5	TSL:6	c.225C>A	p.Ser75Arg	missense	Exon 2 of 5	ENSP00000378767.1

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

GnomAD2 exomes AF: 0.130 AC: 21202 AN: 163220 AF XY: 0.129

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 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

African (AFR) AF: 0.0106 AC: 253 AN: 23760

American (AMR) AF: 0.0408 AC: 777 AN: 19034

Ashkenazi Jewish (ASJ) AF: 0.0171 AC: 257 AN: 15062

East Asian (EAS) AF: 0.0124 AC: 319 AN: 25680

South Asian (SAS) AF: 0.0252 AC: 1559 AN: 61944

European-Finnish (FIN) AF: 0.0172 AC: 631 AN: 36672

Middle Eastern (MID) AF: 0.0343 AC: 108 AN: 3152

European-Non Finnish (NFE) AF: 0.00801 AC: 5540 AN: 691712

Other (OTH) AF: 0.0105 AC: 402 AN: 38454

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

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

African (AFR) AF: 0.0209 AC: 474 AN: 22658

American (AMR) AF: 0.0201 AC: 127 AN: 6332

Ashkenazi Jewish (ASJ) AF: 0.0245 AC: 39 AN: 1592

East Asian (EAS) AF: 0.0119 AC: 30 AN: 2514

South Asian (SAS) AF: 0.0143 AC: 37 AN: 2592

European-Finnish (FIN) AF: 0.0118 AC: 70 AN: 5944

Middle Eastern (MID) AF: 0.0455 AC: 5 AN: 110

European-Non Finnish (NFE) AF: 0.0255 AC: 891 AN: 34994

Other (OTH) AF: 0.0266 AC: 26 AN: 976

⚠️ 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: 0.104 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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	7.9
DANN	Benign	0.91
DEOGEN2	Benign	0.011	T
Eigen	Benign	-0.97
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.046	N
LIST_S2	Benign	0.67	T
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-0.92	T
PhyloP100		-1.2
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.028
Sift	Benign	0.19	T
Sift4G	Benign	0.10	T
Vest4		0.12
MutPred		0.34		Gain of sheet (P = 0.0344)
MPC		0.96
ClinPred		0.0059	T
GERP RS		-0.34
gMVP		0.41
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: rs9272699; hg19: chr6-32609229; COSMIC: COSV58238932; COSMIC: COSV58238932;