6-32638949-A-G

Variant names:

• chr6-32638949-A-G
• rs1246001026
• NM_002122.5:c.82+1409A>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_002122.5(HLA-DQA1):​c.82+1409A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0010 (12 hom., cov: 18)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: HLA-DQA1 NM_002122.5 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0510
• 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: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 6-32638949-A-G is Benign according to our data. Variant chr6-32638949-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 2656469.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-DQA1	NM_002122.5	c.82+1409A>G		intron_variant	Intron 1 of 4	ENST00000343139.11	NP_002113.2
HLA-DQA1-AS1	XR_007059544.1	n.1214T>C		non_coding_transcript_exon_variant	Exon 2 of 2
HLA-DQA1	XM_006715079.5	c.82+1409A>G		intron_variant	Intron 1 of 3		XP_006715142.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLA-DQA1	ENST00000343139.11	c.82+1409A>G		intron_variant	Intron 1 of 4	6	NM_002122.5	ENSP00000339398.5

Frequencies

GnomAD3 genomes AF: 0.000998 AC: 118 AN: 118232 Hom.: 12 Cov.: 18

Gnomad AFR AF: 0.000852

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000630

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000233

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00151

Gnomad OTH AF: 0.000659

GnomAD2 exomes AF: 0.0000310 AC: 3 AN: 96792 AF XY: 0.0000376

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000547

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000165 AC: 4 AN: 241736 Hom.: 0 Cov.: 0 AF XY: 0.00000722 AC XY: 1 AN XY: 138594

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

African (AFR) AF: 0.00 AC: 0 AN: 6818

American (AMR) AF: 0.00 AC: 0 AN: 20620

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8454

East Asian (EAS) AF: 0.00 AC: 0 AN: 7712

South Asian (SAS) AF: 0.00 AC: 0 AN: 46310

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10472

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2048

European-Non Finnish (NFE) AF: 0.0000235 AC: 3 AN: 127864

Other (OTH) AF: 0.0000874 AC: 1 AN: 11438

⚠️ 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 AF: 0.000997 AC: 118 AN: 118356 Hom.: 12 Cov.: 18 AF XY: 0.000902 AC XY: 52 AN XY: 57678

African (AFR) AF: 0.000849 AC: 27 AN: 31810

American (AMR) AF: 0.000629 AC: 7 AN: 11120

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2732

East Asian (EAS) AF: 0.00 AC: 0 AN: 4380

South Asian (SAS) AF: 0.00 AC: 0 AN: 3540

European-Finnish (FIN) AF: 0.000233 AC: 2 AN: 8592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 176

European-Non Finnish (NFE) AF: 0.00151 AC: 81 AN: 53750

Other (OTH) AF: 0.000650 AC: 1 AN: 1538

Alfa AF: 0.00135 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Feb 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

HLA-DQA1: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	5.8
DANN	Benign	0.57
PhyloP100		-0.051
Mutation Taster		=100/0	polymorphism

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: rs1246001026; hg19: chr6-32606726;