6-32641349-T-G

Variant names:

• chr6-32641349-T-G
• rs1071630
• NM_002122.5:c.122T>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002122.5(HLA-DQA1):​c.122T>G​(p.Phe41Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000996 in 1,004,180 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 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. F41S) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 15)
  • Exomes 𝑓: 0.0000010 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-DQA1 NM_002122.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.905
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15876356).

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.122T>G	p.Phe41Cys	missense	Exon 2 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.122T>G	p.Phe41Cys	missense	Exon 2 of 5	ENSP00000339398.5
	HLA-DQA1	ENST00000374949.2	TSL:6	c.122T>G	p.Phe41Cys	missense	Exon 2 of 4	ENSP00000364087.2
	HLA-DQA1	ENST00000395363.5	TSL:6	c.122T>G	p.Phe41Cys	missense	Exon 2 of 5	ENSP00000378767.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 97566 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: 9.96e-7 AC: 1 AN: 1004180 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 510546

⚠️ 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: 25156

American (AMR) AF: 0.00 AC: 0 AN: 31892

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18708

East Asian (EAS) AF: 0.00 AC: 0 AN: 28072

South Asian (SAS) AF: 0.00 AC: 0 AN: 76266

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43064

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4074

European-Non Finnish (NFE) AF: 0.00000136 AC: 1 AN: 735258

Other (OTH) AF: 0.00 AC: 0 AN: 41690

⚠️ 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: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 97566 Hom.: 0 Cov.: 15 AF XY: 0.00 AC XY: 0 AN XY: 47296

African (AFR) AF: 0.00 AC: 0 AN: 27508

American (AMR) AF: 0.00 AC: 0 AN: 7688

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2162

East Asian (EAS) AF: 0.00 AC: 0 AN: 2870

South Asian (SAS) AF: 0.00 AC: 0 AN: 3084

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 150

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 45566

Other (OTH) AF: 0.00 AC: 0 AN: 1274

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0077	T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.077	N
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.0024	T
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-1.1	T
PhyloP100		0.91
PrimateAI	Benign	0.43	T
PROVEAN	Benign	0.27	N
REVEL	Benign	0.16
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.021	D
Vest4		0.22
MutPred		0.39		Loss of stability (P = 0.0588)
MVP		0.095
MPC		1.5
ClinPred		0.98	D
GERP RS		3.0
gMVP		0.74
Mutation Taster		=99/1	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: rs1071630; hg19: chr6-32609126;