NM_002122.5:c.557T>G

Variant names:

• chr6-32642197-T-G
• rs707962
• NM_002122.5:c.557T>G

Variant summary

Our verdict is Likely benign. The variant received -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. 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 0.018 (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
• Publications: 28 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]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

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

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.557T>G	p.Ile186Ser	missense	Exon 3 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.557T>G	p.Ile186Ser	missense	Exon 3 of 5	ENSP00000339398.5
	HLA-DQA1	ENST00000374949.2	TSL:6	c.557T>G	p.Ile186Ser	missense	Exon 3 of 4	ENSP00000364087.2
	HLA-DQA1	ENST00000395363.5	TSL:6	c.557T>G	p.Ile186Ser	missense	Exon 3 of 5	ENSP00000378767.1

Frequencies

GnomAD3 genomes AF: 0.0180 AC: 1622 AN: 90310 Hom.: 15 Cov.: 16

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

GnomAD2 exomes AF: 0.161 AC: 32767 AN: 203358 AF XY: 0.164

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 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

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

African (AFR) AF: 0.0557 AC: 1455 AN: 26138

American (AMR) AF: 0.158 AC: 5918 AN: 37414

Ashkenazi Jewish (ASJ) AF: 0.135 AC: 2682 AN: 19932

East Asian (EAS) AF: 0.0506 AC: 1717 AN: 33936

South Asian (SAS) AF: 0.132 AC: 8966 AN: 68148

European-Finnish (FIN) AF: 0.0530 AC: 2381 AN: 44956

Middle Eastern (MID) AF: 0.118 AC: 479 AN: 4076

European-Non Finnish (NFE) AF: 0.0639 AC: 52245 AN: 817936

Other (OTH) AF: 0.0785 AC: 3628 AN: 46202

⚠️ 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 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

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

African (AFR) AF: 0.0142 AC: 364 AN: 25592

American (AMR) AF: 0.0186 AC: 145 AN: 7808

Ashkenazi Jewish (ASJ) AF: 0.0260 AC: 50 AN: 1922

East Asian (EAS) AF: 0.00916 AC: 27 AN: 2946

South Asian (SAS) AF: 0.0152 AC: 47 AN: 3082

European-Finnish (FIN) AF: 0.0102 AC: 69 AN: 6780

Middle Eastern (MID) AF: 0.0242 AC: 3 AN: 124

European-Non Finnish (NFE) AF: 0.0222 AC: 897 AN: 40348

Other (OTH) AF: 0.0111 AC: 13 AN: 1176

⚠️ 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: 0.153 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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
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
MetaRNN	Benign	0.0022	T
MetaSVM	Benign	-0.96	T
PhyloP100		0.89
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.11
Sift	Benign	0.060	T
Sift4G	Benign	0.19	T
Vest4		0.11
MPC		1.2
ClinPred		0.0077	T
GERP RS		2.9
gMVP		0.80
Mutation Taster		=96/4	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: rs707962; hg19: chr6-32609974; COSMIC: COSV58242233; COSMIC: COSV58242233;