rs8084

Positions:

• chr6-32443258-A-C
• chr6-32443258-A-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The NM_019111.5(HLA-DRA):​c.402A>C​(p.Ile134=) 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. Variant has been reported in Lovd as Benign (no stars).

• 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

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_addAF=-0.911607).
• BP6: Variant 6-32443258-A-C is Benign according to our data. Variant chr6-32443258-A-C is described in Lovd as [Benign].
• 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/exons	MANE	Protein	UniProt
HLA-DRA	NM_019111.5	c.402A>C	p.Ile134=	synonymous_variant	3/5	ENST00000395388.7	NP_061984.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HLA-DRA	ENST00000395388.7	c.402A>C	p.Ile134=	synonymous_variant	3/5		NM_019111.5	ENSP00000378786	P1
HLA-DRA	ENST00000374982.5	c.329-2A>C		splice_acceptor_variant				ENSP00000364121

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

GnomAD3 exomes AF: 0.611 AC: 150710 AN: 246556 Hom.: 47059 AF XY: 0.618 AC XY: 83027 AN XY: 134378

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 SAS exome AF: 0.717

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

Gnomad4 AFR exome AF: 0.586

Gnomad4 AMR exome AF: 0.623

Gnomad4 ASJ exome AF: 0.719

Gnomad4 EAS exome AF: 0.656

Gnomad4 SAS exome AF: 0.717

Gnomad4 FIN exome AF: 0.508

Gnomad4 NFE exome AF: 0.567

Gnomad4 OTH exome AF: 0.589

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

Gnomad4 AFR AF: 0.591

Gnomad4 AMR AF: 0.658

Gnomad4 ASJ AF: 0.730

Gnomad4 EAS AF: 0.698

Gnomad4 SAS AF: 0.685

Gnomad4 FIN AF: 0.505

Gnomad4 NFE AF: 0.567

Gnomad4 OTH AF: 0.630

Alfa AF: 0.581 Hom.: 36812

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
MutationTaster	Benign	0.00017	P;P
GERP RS		-9.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs8084; hg19: chr6-32411035; COSMIC: COSV66622864;