chr6-32443258-A-C

Variant names:

• chr6-32443258-A-C
• rs8084
• NM_019111.5:c.402A>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_019111.5(HLA-DRA):​c.402A>C​(p.Ile134Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.583 in 1,611,822 control chromosomes in the GnomAD database, including 277,896 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 0.59 (26922 hom., cov: 30)
  • Exomes 𝑓: 0.58 (250974 hom.)
• Consequence: HLA-DRA NM_019111.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.39
• Publications: 74 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_addAF=-0.911607).
• BP7: Synonymous conserved (PhyloP=-3.39 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.679 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-DRA	NM_019111.5	c.402A>C	p.Ile134Ile	synonymous_variant	Exon 3 of 5	ENST00000395388.7	NP_061984.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLA-DRA	ENST00000395388.7	c.402A>C	p.Ile134Ile	synonymous_variant	Exon 3 of 5	6	NM_019111.5	ENSP00000378786.2
HLA-DRA	ENST00000374982.5	c.329-2A>C		splice_acceptor_variant, intron_variant	Intron 2 of 4	6		ENSP00000364121.5
ENSG00000299747	ENST00000766007.1	n.163-4998T>G		intron_variant	Intron 1 of 2

Frequencies

GnomAD3 genomes AF: 0.592 AC: 89777 AN: 151748 Hom.: 26903 Cov.: 30

Gnomad AFR AF: 0.591

Gnomad AMI AF: 0.610

Gnomad AMR AF: 0.658

Gnomad ASJ AF: 0.730

Gnomad EAS AF: 0.699

Gnomad SAS AF: 0.684

Gnomad FIN AF: 0.505

Gnomad MID AF: 0.715

Gnomad NFE AF: 0.567

Gnomad OTH AF: 0.628

GnomAD2 exomes AF: 0.611 AC: 150710 AN: 246556 AF XY: 0.618

Gnomad AFR exome AF: 0.589

Gnomad AMR exome AF: 0.614

Gnomad ASJ exome AF: 0.725

Gnomad EAS exome AF: 0.720

Gnomad FIN exome AF: 0.510

Gnomad NFE exome AF: 0.575

Gnomad OTH exome AF: 0.618

GnomAD4 exome AF: 0.582 AC: 850280 AN: 1459956 Hom.: 250974 Cov.: 44 AF XY: 0.588 AC XY: 426854 AN XY: 726322

African (AFR) AF: 0.586 AC: 19626 AN: 33474

American (AMR) AF: 0.623 AC: 27855 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.719 AC: 18800 AN: 26130

East Asian (EAS) AF: 0.656 AC: 26037 AN: 39698

South Asian (SAS) AF: 0.717 AC: 61817 AN: 86242

European-Finnish (FIN) AF: 0.508 AC: 26550 AN: 52306

Middle Eastern (MID) AF: 0.730 AC: 4213 AN: 5768

European-Non Finnish (NFE) AF: 0.567 AC: 629833 AN: 1111260

Other (OTH) AF: 0.589 AC: 35549 AN: 60358

GnomAD4 genome AF: 0.592 AC: 89839 AN: 151866 Hom.: 26922 Cov.: 30 AF XY: 0.593 AC XY: 44034 AN XY: 74198

African (AFR) AF: 0.591 AC: 24447 AN: 41394

American (AMR) AF: 0.658 AC: 10042 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.730 AC: 2533 AN: 3468

East Asian (EAS) AF: 0.698 AC: 3590 AN: 5140

South Asian (SAS) AF: 0.685 AC: 3297 AN: 4810

European-Finnish (FIN) AF: 0.505 AC: 5331 AN: 10564

Middle Eastern (MID) AF: 0.707 AC: 208 AN: 294

European-Non Finnish (NFE) AF: 0.567 AC: 38506 AN: 67910

Other (OTH) AF: 0.630 AC: 1330 AN: 2110

Alfa AF: 0.579 Hom.: 90278

Bravo AF: 0.604

TwinsUK AF: 0.566 AC: 2100

ALSPAC AF: 0.585 AC: 2253

ESP6500AA AF: 0.572 AC: 1728

ESP6500EA AF: 0.569 AC: 3084

ExAC AF: 0.607 AC: 71560

Asia WGS AF: 0.673 AC: 2345 AN: 3478

EpiCase AF: 0.607

EpiControl AF: 0.621

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.91	T
BayesDel_noAF	Benign	-0.94
CADD	Benign	2.4
DANN	Benign	0.45
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0069	N
PhyloP100		-3.4
GERP RS		-9.7
Mutation Taster		=66/34	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs8084; hg19: chr6-32411035; COSMIC: COSV66622864;