6-33075743-C-G

Variant names:

• chr6-33075743-C-G
• rs2071349
• NM_001242524.2:c.-99-2074G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001242524.2(HLA-DPA1):​c.-99-2074G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.142 in 152,090 control chromosomes in the GnomAD database, including 1,624 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.14 (1624 hom., cov: 32)
• Consequence: HLA-DPA1 NM_001242524.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.619
• Publications: 20 publications found

Genes affected

HLA-DPA1 (HGNC:4938): (major histocompatibility complex, class II, DP alpha 1) HLA-DPA1 belongs to the HLA class II alpha chain paralogues. This class II molecule is a heterodimer consisting of an alpha (DPA) and a beta (DPB) chain, 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 and its gene contains 5 exons. Exon one encodes the leader peptide, exons 2 and 3 encode the two extracellular domains, exon 4 encodes the transmembrane domain and the cytoplasmic tail. Within the DP molecule both the alpha chain and the beta chain contain the polymorphisms specifying the peptide binding specificities, resulting in up to 4 different molecules. [provided by RefSeq, Jul 2008]

HLA-DPB1 (HGNC:4940): (major histocompatibility complex, class II, DP beta 1) HLA-DPB belongs to the HLA class II beta chain paralogues. This class II molecule is a heterodimer consisting of an alpha (DPA) and a beta chain (DPB), 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 beta chain is approximately 26-28 kDa and its gene contains 6 exons. Exon one encodes the leader peptide, exons 2 and 3 encode the two extracellular domains, exon 4 encodes the transmembrane domain and exon 5 encodes the cytoplasmic tail. Within the DP molecule both the alpha chain and the beta chain contain the polymorphisms specifying the peptide binding specificities, resulting in up to 4 different molecules. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.193 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-DPA1	NM_001242524.2	c.-99-2074G>C		intron_variant	Intron 1 of 5		NP_001229453.1
HLA-DPA1	NM_001242525.2	c.-23-2150G>C		intron_variant	Intron 1 of 5		NP_001229454.1
HLA-DPB1	NM_002121.6	c.-299C>G		upstream_gene_variant		ENST00000418931.7	NP_002112.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLA-DPB1	ENST00000418931.7	c.-299C>G		upstream_gene_variant		6	NM_002121.6	ENSP00000408146.2

Frequencies

GnomAD3 genomes AF: 0.142 AC: 21564 AN: 151972 Hom.: 1622 Cov.: 32

Gnomad AFR AF: 0.148

Gnomad AMI AF: 0.0833

Gnomad AMR AF: 0.133

Gnomad ASJ AF: 0.163

Gnomad EAS AF: 0.149

Gnomad SAS AF: 0.204

Gnomad FIN AF: 0.142

Gnomad MID AF: 0.256

Gnomad NFE AF: 0.134

Gnomad OTH AF: 0.163

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.142 AC: 21577 AN: 152090 Hom.: 1624 Cov.: 32 AF XY: 0.145 AC XY: 10754 AN XY: 74352

African (AFR) AF: 0.148 AC: 6136 AN: 41464

American (AMR) AF: 0.133 AC: 2029 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.163 AC: 565 AN: 3468

East Asian (EAS) AF: 0.149 AC: 772 AN: 5184

South Asian (SAS) AF: 0.204 AC: 980 AN: 4810

European-Finnish (FIN) AF: 0.142 AC: 1498 AN: 10584

Middle Eastern (MID) AF: 0.241 AC: 71 AN: 294

European-Non Finnish (NFE) AF: 0.134 AC: 9107 AN: 67986

Other (OTH) AF: 0.162 AC: 343 AN: 2114

Alfa AF: 0.0778 Hom.: 127

Bravo AF: 0.141

Asia WGS AF: 0.190 AC: 662 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	6.1
DANN	Benign	0.41
PhyloP100		0.62
PromoterAI		0.032	Neutral
Mutation Taster		=100/0	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: rs2071349; hg19: chr6-33043520;