6-32581724-A-T

Position:

• chr6-32581724-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002124.4(HLA-DRB1):​c.485T>A​(p.Leu162Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L162R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.23 (6 hom., cov: 17)
  • Exomes 𝑓: 0.27 (469 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-DRB1 NM_002124.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.268

Genes affected

HLA-DRB1 (HGNC:4948): (major histocompatibility complex, class II, DR beta 1) HLA-DRB1 belongs to the HLA class II beta chain paralogs. The class II molecule is a heterodimer consisting of an alpha (DRA) and a beta chain (DRB), 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. The beta chain is approximately 26-28 kDa. It is encoded by 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 DR molecule the beta chain contains all the polymorphisms specifying the peptide binding specificities. Hundreds of DRB1 alleles have been described and some alleles have increased frequencies associated with certain diseases or conditions. For example, DRB1*1302 has been related to acute and chronic hepatitis B virus persistence. There are multiple pseudogenes of this gene. [provided by RefSeq, Jul 2020]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018897653).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.287 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HLA-DRB1	NM_002124.4	c.485T>A	p.Leu162Gln	missense_variant	3/6	ENST00000360004.6	NP_002115.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HLA-DRB1	ENST00000360004.6	c.485T>A	p.Leu162Gln	missense_variant	3/6		NM_002124.4	ENSP00000353099	P1

Frequencies

GnomAD3 genomes AF: 0.227 AC: 23906 AN: 105462 Hom.: 6 Cov.: 17

Gnomad AFR AF: 0.174

Gnomad AMI AF: 0.287

Gnomad AMR AF: 0.287

Gnomad ASJ AF: 0.266

Gnomad EAS AF: 0.301

Gnomad SAS AF: 0.201

Gnomad FIN AF: 0.217

Gnomad MID AF: 0.245

Gnomad NFE AF: 0.235

Gnomad OTH AF: 0.244

GnomAD3 exomes AF: 0.198 AC: 42988 AN: 216838 Hom.: 1 AF XY: 0.197 AC XY: 23289 AN XY: 118260

Gnomad AFR exome AF: 0.133

Gnomad AMR exome AF: 0.250

Gnomad ASJ exome AF: 0.233

Gnomad EAS exome AF: 0.206

Gnomad SAS exome AF: 0.141

Gnomad FIN exome AF: 0.159

Gnomad NFE exome AF: 0.210

Gnomad OTH exome AF: 0.203

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR;InbreedingCoeff AF: 0.273 AC: 317643 AN: 1163264 Hom.: 469 Cov.: 34 AF XY: 0.267 AC XY: 156650 AN XY: 587524

Gnomad4 AFR exome AF: 0.167

Gnomad4 AMR exome AF: 0.289

Gnomad4 ASJ exome AF: 0.260

Gnomad4 EAS exome AF: 0.279

Gnomad4 SAS exome AF: 0.186

Gnomad4 FIN exome AF: 0.189

Gnomad4 NFE exome AF: 0.289

Gnomad4 OTH exome AF: 0.252

GnomAD4 genome AF: 0.227 AC: 23919 AN: 105552 Hom.: 6 Cov.: 17 AF XY: 0.228 AC XY: 11591 AN XY: 50738

Gnomad4 AFR AF: 0.174

Gnomad4 AMR AF: 0.287

Gnomad4 ASJ AF: 0.266

Gnomad4 EAS AF: 0.302

Gnomad4 SAS AF: 0.200

Gnomad4 FIN AF: 0.217

Gnomad4 NFE AF: 0.234

Gnomad4 OTH AF: 0.242

Alfa AF: 0.114 Hom.: 5266

ExAC AF: 0.199 AC: 24116

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.048
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.10
CADD	Benign	18
DANN	Benign	0.94
DEOGEN2	Benign	0.0065	T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.072	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	1.0	N
PROVEAN	Benign	1.8	N
REVEL	Benign	0.20
Sift	Uncertain	0.013	D
Sift4G	Benign	0.26	T
Polyphen		0.53	P
Vest4		0.042
MPC		0.76
ClinPred		0.0032	T
GERP RS		-0.19
Varity_R		0.27
gMVP		0.33

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

Publications

LitVar

Other links and lift over

dbSNP: rs707954; hg19: chr6-32549501; COSMIC: COSV63513460;