6-32443746-T-C

Variant names:

• chr6-32443746-T-C
• rs2239804
• NM_019111.5:c.611-10T>C

Variant summary

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

The NM_019111.5(HLA-DRA):​c.611-10T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.472 in 1,564,834 control chromosomes in the GnomAD database, including 180,174 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 0.49 (18830 hom., cov: 31)
  • Exomes 𝑓: 0.47 (161344 hom.)
• Consequence: HLA-DRA NM_019111.5 intron
• Scores: Splicing: ADA: 0.0005100
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.395
• Publications: 67 publications found

Genes affected

HLA-DRA (HGNC:4947): (major histocompatibility complex, class II, DR alpha) HLA-DRA is one of the HLA class II alpha chain paralogues. This class II molecule is a heterodimer consisting of an alpha and a beta chain, both anchored in the membrane. This molecule is expressed on the surface of various antigen presenting cells such as B lymphocytes, dendritic cells, and monocytes/macrophages, and plays a central role in the immune system and response by presenting peptides derived from extracellular proteins, in particular, pathogen-derived peptides to T cells. The alpha chain is approximately 33-35 kDa and its gene contains 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. DRA does not have polymorphisms in the peptide binding part and acts as the sole alpha chain for DRB1, DRB3, DRB4 and DRB5. [provided by RefSeq, Aug 2020]

ENSG00000299747 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.646 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-DRA	NM_019111.5	c.611-10T>C		intron_variant	Intron 3 of 4	ENST00000395388.7	NP_061984.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLA-DRA	ENST00000395388.7	c.611-10T>C		intron_variant	Intron 3 of 4	6	NM_019111.5	ENSP00000378786.2
HLA-DRA	ENST00000374982.5	c.536-10T>C		intron_variant	Intron 3 of 4	6		ENSP00000364121.5
ENSG00000299747	ENST00000766007.1	n.163-5486A>G		intron_variant	Intron 1 of 2

Frequencies

GnomAD3 genomes AF: 0.489 AC: 74280 AN: 151866 Hom.: 18820 Cov.: 31

Gnomad AFR AF: 0.512

Gnomad AMI AF: 0.390

Gnomad AMR AF: 0.564

Gnomad ASJ AF: 0.685

Gnomad EAS AF: 0.664

Gnomad SAS AF: 0.601

Gnomad FIN AF: 0.297

Gnomad MID AF: 0.668

Gnomad NFE AF: 0.456

Gnomad OTH AF: 0.524

GnomAD2 exomes AF: 0.507 AC: 107239 AN: 211414 AF XY: 0.512

Gnomad AFR exome AF: 0.510

Gnomad AMR exome AF: 0.547

Gnomad ASJ exome AF: 0.675

Gnomad EAS exome AF: 0.684

Gnomad FIN exome AF: 0.308

Gnomad NFE exome AF: 0.464

Gnomad OTH exome AF: 0.515

GnomAD4 exome AF: 0.470 AC: 663567 AN: 1412850 Hom.: 161344 Cov.: 33 AF XY: 0.476 AC XY: 332877 AN XY: 699732

African (AFR) AF: 0.509 AC: 16231 AN: 31880

American (AMR) AF: 0.554 AC: 20474 AN: 36980

Ashkenazi Jewish (ASJ) AF: 0.673 AC: 15581 AN: 23164

East Asian (EAS) AF: 0.606 AC: 23766 AN: 39212

South Asian (SAS) AF: 0.631 AC: 49101 AN: 77786

European-Finnish (FIN) AF: 0.308 AC: 15719 AN: 51080

Middle Eastern (MID) AF: 0.681 AC: 3774 AN: 5540

European-Non Finnish (NFE) AF: 0.450 AC: 490299 AN: 1088764

Other (OTH) AF: 0.490 AC: 28622 AN: 58444

GnomAD4 genome AF: 0.489 AC: 74326 AN: 151984 Hom.: 18830 Cov.: 31 AF XY: 0.487 AC XY: 36157 AN XY: 74276

African (AFR) AF: 0.512 AC: 21211 AN: 41424

American (AMR) AF: 0.564 AC: 8611 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.685 AC: 2378 AN: 3470

East Asian (EAS) AF: 0.664 AC: 3438 AN: 5176

South Asian (SAS) AF: 0.602 AC: 2890 AN: 4804

European-Finnish (FIN) AF: 0.297 AC: 3142 AN: 10564

Middle Eastern (MID) AF: 0.663 AC: 195 AN: 294

European-Non Finnish (NFE) AF: 0.456 AC: 30991 AN: 67958

Other (OTH) AF: 0.528 AC: 1116 AN: 2114

Alfa AF: 0.491 Hom.: 56722

Bravo AF: 0.511

Asia WGS AF: 0.597 AC: 2073 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	7.0
DANN	Benign	0.73
PhyloP100		0.40
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00051
dbscSNV1_RF	Benign	0.012
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: rs2239804; hg19: chr6-32411523; COSMIC: COSV66622831;