rs707962

Positions:

• chr6-32642197-T-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_002122.5(HLA-DQA1):​c.557T>G​(p.Ile186Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 10/17 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 0.018 (14 hom., cov: 16)
  • Exomes 𝑓: 0.072 (13971 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-DQA1 NM_002122.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.888

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0022393465).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HLA-DQA1	NM_002122.5	c.557T>G	p.Ile186Ser	missense_variant	3/5	ENST00000343139.11	NP_002113.2
HLA-DQA1	XM_006715079.5	c.557T>G	p.Ile186Ser	missense_variant	3/4		XP_006715142.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HLA-DQA1	ENST00000343139.11	c.557T>G	p.Ile186Ser	missense_variant	3/5		NM_002122.5	ENSP00000339398	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 1622 AN: 90310 Hom.: 15 Cov.: 16 FAILED QC

Gnomad AFR AF: 0.0143

Gnomad AMI AF: 0.0113

Gnomad AMR AF: 0.0186

Gnomad ASJ AF: 0.0260

Gnomad EAS AF: 0.00914

Gnomad SAS AF: 0.0152

Gnomad FIN AF: 0.0102

Gnomad MID AF: 0.0234

Gnomad NFE AF: 0.0222

Gnomad OTH AF: 0.0112

GnomAD3 exomes AF: 0.161 AC: 32767 AN: 203358 Hom.: 6402 AF XY: 0.164 AC XY: 18093 AN XY: 110266

Gnomad AFR exome AF: 0.119

Gnomad AMR exome AF: 0.204

Gnomad ASJ exome AF: 0.230

Gnomad EAS exome AF: 0.119

Gnomad SAS exome AF: 0.183

Gnomad FIN exome AF: 0.0932

Gnomad NFE exome AF: 0.162

Gnomad OTH exome AF: 0.169

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0723 AC: 79471 AN: 1098738 Hom.: 13971 Cov.: 33 AF XY: 0.0769 AC XY: 42264 AN XY: 549604

Gnomad4 AFR exome AF: 0.0557

Gnomad4 AMR exome AF: 0.158

Gnomad4 ASJ exome AF: 0.135

Gnomad4 EAS exome AF: 0.0506

Gnomad4 SAS exome AF: 0.132

Gnomad4 FIN exome AF: 0.0530

Gnomad4 NFE exome AF: 0.0639

Gnomad4 OTH exome AF: 0.0785

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0179 AC: 1622 AN: 90396 Hom.: 14 Cov.: 16 AF XY: 0.0165 AC XY: 729 AN XY: 44170

Gnomad4 AFR AF: 0.0142

Gnomad4 AMR AF: 0.0186

Gnomad4 ASJ AF: 0.0260

Gnomad4 EAS AF: 0.00916

Gnomad4 SAS AF: 0.0152

Gnomad4 FIN AF: 0.0102

Gnomad4 NFE AF: 0.0222

Gnomad4 OTH AF: 0.0111

Alfa AF: 0.153 Hom.: 756

ESP6500AA AF: 0.117 AC: 353

ESP6500EA AF: 0.140 AC: 759

ExAC AF: 0.202 AC: 23607

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.47
CADD	Uncertain	25
DANN	Benign	0.94
DEOGEN2	Benign	0.012	.;.;T;.
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.61	.;.;T;T
MetaRNN	Benign	0.0022	T;T;T;T
MetaSVM	Benign	-0.96	T
MutationTaster	Benign	0.0013	P;P;P;P
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-3.0	D;D;D;D
REVEL	Benign	0.11
Sift	Benign	0.060	T;T;T;T
Sift4G	Benign	0.19	T;T;T;T
Vest4		0.11
MPC		1.2
ClinPred		0.0077	T
GERP RS		2.9
gMVP		0.80

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

Publications

LitVar

Other links and lift over

dbSNP: rs707962; hg19: chr6-32609974; COSMIC: COSV58242233; COSMIC: COSV58242233;