6-32443869-T-G

Variant names:

• chr6-32443869-T-G
• rs7192
• NM_019111.5:c.724T>G

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.724T>G​(p.Leu242Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.618 in 1,608,860 control chromosomes in the GnomAD database, including 310,908 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.62 (29220 hom., cov: 31)
  • Exomes 𝑓: 0.62 (281688 hom.)
• Consequence: HLA-DRA NM_019111.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0130
• Publications: 144 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 (MetaRNN=1.4552423E-6).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.722 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-DRA	NM_019111.5	c.724T>G	p.Leu242Val	missense_variant	Exon 4 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.724T>G	p.Leu242Val	missense_variant	Exon 4 of 5	6	NM_019111.5	ENSP00000378786.2
HLA-DRA	ENST00000374982.5	c.649T>G	p.Leu217Val	missense_variant	Exon 4 of 5	6		ENSP00000364121.5
ENSG00000299747	ENST00000766007.1	n.163-5609A>C		intron_variant	Intron 1 of 2

Frequencies

GnomAD3 genomes AF: 0.616 AC: 93579 AN: 151850 Hom.: 29201 Cov.: 31

Gnomad AFR AF: 0.598

Gnomad AMI AF: 0.781

Gnomad AMR AF: 0.671

Gnomad ASJ AF: 0.747

Gnomad EAS AF: 0.707

Gnomad SAS AF: 0.741

Gnomad FIN AF: 0.517

Gnomad MID AF: 0.728

Gnomad NFE AF: 0.604

Gnomad OTH AF: 0.650

GnomAD2 exomes AF: 0.637 AC: 155681 AN: 244280 AF XY: 0.647

Gnomad AFR exome AF: 0.595

Gnomad AMR exome AF: 0.623

Gnomad ASJ exome AF: 0.738

Gnomad EAS exome AF: 0.724

Gnomad FIN exome AF: 0.522

Gnomad NFE exome AF: 0.610

Gnomad OTH exome AF: 0.641

GnomAD4 exome AF: 0.618 AC: 900436 AN: 1456892 Hom.: 281688 Cov.: 44 AF XY: 0.624 AC XY: 451887 AN XY: 724648

African (AFR) AF: 0.594 AC: 19816 AN: 33378

American (AMR) AF: 0.633 AC: 28036 AN: 44292

Ashkenazi Jewish (ASJ) AF: 0.733 AC: 19075 AN: 26010

East Asian (EAS) AF: 0.659 AC: 26101 AN: 39622

South Asian (SAS) AF: 0.768 AC: 65659 AN: 85534

European-Finnish (FIN) AF: 0.522 AC: 27273 AN: 52260

Middle Eastern (MID) AF: 0.746 AC: 4295 AN: 5758

European-Non Finnish (NFE) AF: 0.606 AC: 672693 AN: 1109812

Other (OTH) AF: 0.622 AC: 37488 AN: 60226

GnomAD4 genome AF: 0.616 AC: 93641 AN: 151968 Hom.: 29220 Cov.: 31 AF XY: 0.617 AC XY: 45848 AN XY: 74272

African (AFR) AF: 0.597 AC: 24759 AN: 41452

American (AMR) AF: 0.671 AC: 10253 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.747 AC: 2592 AN: 3470

East Asian (EAS) AF: 0.706 AC: 3651 AN: 5168

South Asian (SAS) AF: 0.742 AC: 3575 AN: 4816

European-Finnish (FIN) AF: 0.517 AC: 5440 AN: 10524

Middle Eastern (MID) AF: 0.721 AC: 212 AN: 294

European-Non Finnish (NFE) AF: 0.604 AC: 41074 AN: 67948

Other (OTH) AF: 0.652 AC: 1373 AN: 2106

Alfa AF: 0.615 Hom.: 132555

Bravo AF: 0.627

TwinsUK AF: 0.602 AC: 2233

ALSPAC AF: 0.623 AC: 2400

ESP6500AA AF: 0.580 AC: 1752

ESP6500EA AF: 0.608 AC: 3292

ExAC AF: 0.635 AC: 74857

Asia WGS AF: 0.692 AC: 2410 AN: 3478

EpiCase AF: 0.645

EpiControl AF: 0.655

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.85	T
BayesDel_noAF	Benign	-0.85
CADD	Benign	4.7
DANN	Benign	0.54
DEOGEN2	Benign	0.0051	.;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.011	N
MetaRNN	Benign	0.0000015	T;T
MetaSVM	Benign	-0.92	T
PhyloP100		-0.013
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.71	N;N
REVEL	Benign	0.011
Sift	Benign	0.28	T;T
Sift4G	Benign	0.47	T;T
Polyphen		0.0	.;B
Vest4		0.026
MPC		0.49
ClinPred		0.012	T
GERP RS		-7.3
gMVP		0.26
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: rs7192; hg19: chr6-32411646; COSMIC: COSV66622530;