chr6-32642192-T-G

Variant names:

• chr6-32642192-T-G
• rs707963
• NM_002122.5:c.552T>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.552T>G​(p.Asp184Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/18 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 (16 hom., cov: 16)
  • Exomes 𝑓: 0.079 (14160 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-DQA1 NM_002122.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.16
• Publications: 23 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=0.0018129051).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-DQA1	NM_002122.5	c.552T>G	p.Asp184Glu	missense_variant	Exon 3 of 5	ENST00000343139.11	NP_002113.2
HLA-DQA1	XM_006715079.5	c.552T>G	p.Asp184Glu	missense_variant	Exon 3 of 4		XP_006715142.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLA-DQA1	ENST00000343139.11	c.552T>G	p.Asp184Glu	missense_variant	Exon 3 of 5	6	NM_002122.5	ENSP00000339398.5

Frequencies

GnomAD3 genomes AF: 0.0175 AC: 1571 AN: 89682 Hom.: 17 Cov.: 16

Gnomad AFR AF: 0.0137

Gnomad AMI AF: 0.00825

Gnomad AMR AF: 0.0168

Gnomad ASJ AF: 0.0272

Gnomad EAS AF: 0.00886

Gnomad SAS AF: 0.0172

Gnomad FIN AF: 0.00888

Gnomad MID AF: 0.0303

Gnomad NFE AF: 0.0220

Gnomad OTH AF: 0.0113

GnomAD2 exomes AF: 0.165 AC: 33775 AN: 204164 AF XY: 0.169

Gnomad AFR exome AF: 0.121

Gnomad AMR exome AF: 0.207

Gnomad ASJ exome AF: 0.236

Gnomad EAS exome AF: 0.122

Gnomad FIN exome AF: 0.0964

Gnomad NFE exome AF: 0.166

Gnomad OTH exome AF: 0.175

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0790 AC: 85290 AN: 1079034 Hom.: 14160 Cov.: 33 AF XY: 0.0834 AC XY: 45110 AN XY: 540736

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

African (AFR) AF: 0.0589 AC: 1525 AN: 25888

American (AMR) AF: 0.160 AC: 5985 AN: 37380

Ashkenazi Jewish (ASJ) AF: 0.140 AC: 2786 AN: 19884

East Asian (EAS) AF: 0.0519 AC: 1749 AN: 33728

South Asian (SAS) AF: 0.137 AC: 9254 AN: 67700

European-Finnish (FIN) AF: 0.0544 AC: 2446 AN: 44974

Middle Eastern (MID) AF: 0.125 AC: 502 AN: 4022

European-Non Finnish (NFE) AF: 0.0716 AC: 57238 AN: 799794

Other (OTH) AF: 0.0833 AC: 3805 AN: 45664

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0175 AC: 1573 AN: 89768 Hom.: 16 Cov.: 16 AF XY: 0.0158 AC XY: 693 AN XY: 43800

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

African (AFR) AF: 0.0137 AC: 349 AN: 25472

American (AMR) AF: 0.0167 AC: 130 AN: 7762

Ashkenazi Jewish (ASJ) AF: 0.0272 AC: 52 AN: 1912

East Asian (EAS) AF: 0.00922 AC: 27 AN: 2930

South Asian (SAS) AF: 0.0172 AC: 53 AN: 3084

European-Finnish (FIN) AF: 0.00888 AC: 60 AN: 6756

Middle Eastern (MID) AF: 0.0317 AC: 4 AN: 126

European-Non Finnish (NFE) AF: 0.0220 AC: 880 AN: 39950

Other (OTH) AF: 0.0111 AC: 13 AN: 1170

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.198 Hom.: 762

ESP6500AA AF: 0.128 AC: 387

ESP6500EA AF: 0.155 AC: 838

ExAC AF: 0.202 AC: 23609

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	11
DANN	Benign	0.93
DEOGEN2	Benign	0.00020	.;.;T;.
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.71	.;.;T;T
MetaRNN	Benign	0.0018	T;T;T;T
MetaSVM	Benign	-0.97	T
PhyloP100		-1.2
PrimateAI	Benign	0.46	T
PROVEAN	Benign	0.24	N;N;N;N
REVEL	Benign	0.080
Sift	Benign	0.61	T;T;T;T
Sift4G	Benign	1.0	T;T;T;T
Vest4		0.088
MutPred		0.45		Gain of solvent accessibility (P = 0.1014);Gain of solvent accessibility (P = 0.1014);Gain of solvent accessibility (P = 0.1014);Gain of solvent accessibility (P = 0.1014);
MPC		0.78
ClinPred		0.0021	T
GERP RS		-0.81
gMVP		0.66
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs707963; hg19: chr6-32609969; COSMIC: COSV58239524; COSMIC: COSV58239524;