6-32637511-T-G

Variant names:

• chr6-32637511-T-G
• rs11545686
• NM_002122.5:c.53T>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002122.5(HLA-DQA1):​c.53T>G​(p.Met18Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000289 in 1,072,778 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M18T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 15)
  • Exomes 𝑓: 0.000029 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-DQA1 NM_002122.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.01
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-DQA1	NM_002122.5	c.53T>G	p.Met18Arg	missense_variant	Exon 1 of 5	ENST00000343139.11	NP_002113.2
HLA-DQA1	XM_006715079.5	c.53T>G	p.Met18Arg	missense_variant	Exon 1 of 4		XP_006715142.1
HLA-DQA1-AS1	XR_007059544.1	n.2652A>C		non_coding_transcript_exon_variant	Exon 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLA-DQA1	ENST00000343139.11	c.53T>G	p.Met18Arg	missense_variant	Exon 1 of 5	6	NM_002122.5	ENSP00000339398.5

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 100792 Hom.: 0 Cov.: 15

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000289 AC: 31 AN: 1072778 Hom.: 0 Cov.: 25 AF XY: 0.0000278 AC XY: 15 AN XY: 540408

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

African (AFR) AF: 0.0000349 AC: 1 AN: 28682

American (AMR) AF: 0.00 AC: 0 AN: 35406

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19164

East Asian (EAS) AF: 0.0000342 AC: 1 AN: 29200

South Asian (SAS) AF: 0.0000138 AC: 1 AN: 72392

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3676

European-Non Finnish (NFE) AF: 0.0000328 AC: 26 AN: 793538

Other (OTH) AF: 0.0000443 AC: 2 AN: 45122

⚠️ 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: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 100892 Hom.: 0 Cov.: 15 AF XY: 0.00 AC XY: 0 AN XY: 49228

African (AFR) AF: 0.00 AC: 0 AN: 29886

American (AMR) AF: 0.00 AC: 0 AN: 8432

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2062

East Asian (EAS) AF: 0.00 AC: 0 AN: 3058

South Asian (SAS) AF: 0.00 AC: 0 AN: 3194

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7374

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 152

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 44776

Other (OTH) AF: 0.00 AC: 0 AN: 1334

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.0065	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	17
DANN	Benign	0.88
DEOGEN2	Benign	0.12	.;.;.;T;.
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.024	N
LIST_S2	Uncertain	0.94	D;.;.;D;D
M_CAP	Benign	0.0039	T
MetaRNN	Uncertain	0.56	D;D;D;D;D
MetaSVM	Benign	-0.99	T
PhyloP100		1.0
PrimateAI	Benign	0.34	T
PROVEAN	Pathogenic	-5.8	D;N;N;N;N
REVEL	Benign	0.17
Sift	Pathogenic	0.0	.;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Vest4		0.35, 0.41, 0.41
MutPred		0.72		Loss of sheet (P = 0.007);Loss of sheet (P = 0.007);Loss of sheet (P = 0.007);Loss of sheet (P = 0.007);Loss of sheet (P = 0.007);
MVP		0.15
MPC		1.2
ClinPred		0.50	D
GERP RS		3.0
PromoterAI		-0.0064	Neutral
gMVP		0.73
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs11545686; hg19: chr6-32605288;