NM_002124.4:c.485T>A

Variant names:

• chr6-32581724-A-T
• rs707954
• NM_002124.4:c.485T>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

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. 13/19 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 0.23 (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
• Publications: 26 publications found

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]

HLA-DRB1 Gene-Disease associations (from GenCC):

• systemic lupus erythematosus

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018897653).
• BS2: High Homozygotes in GnomAd4 at 6 Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002124.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLA-DRB1	NM_002124.4	MANE Select	c.485T>A	p.Leu162Gln	missense	Exon 3 of 6	NP_002115.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLA-DRB1	ENST00000360004.6	TSL:6 MANE Select	c.485T>A	p.Leu162Gln	missense	Exon 3 of 6	ENSP00000353099.5
	HLA-DRB1	ENST00000963203.1		c.563T>A	p.Leu188Gln	missense	Exon 3 of 6	ENSP00000633262.1
	HLA-DRB1	ENST00000859900.1		c.485T>A	p.Leu162Gln	missense	Exon 3 of 5	ENSP00000529959.1

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

GnomAD2 exomes AF: 0.198 AC: 42988 AN: 216838 AF XY: 0.197

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 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

African (AFR) AF: 0.167 AC: 4207 AN: 25140

American (AMR) AF: 0.289 AC: 11939 AN: 41258

Ashkenazi Jewish (ASJ) AF: 0.260 AC: 6005 AN: 23076

East Asian (EAS) AF: 0.279 AC: 9866 AN: 35368

South Asian (SAS) AF: 0.186 AC: 14112 AN: 75950

European-Finnish (FIN) AF: 0.189 AC: 9328 AN: 49332

Middle Eastern (MID) AF: 0.246 AC: 1184 AN: 4810

European-Non Finnish (NFE) AF: 0.289 AC: 248634 AN: 859266

Other (OTH) AF: 0.252 AC: 12368 AN: 49064

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

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.174 AC: 4339 AN: 24976

American (AMR) AF: 0.287 AC: 2947 AN: 10272

Ashkenazi Jewish (ASJ) AF: 0.266 AC: 697 AN: 2620

East Asian (EAS) AF: 0.302 AC: 1126 AN: 3734

South Asian (SAS) AF: 0.200 AC: 619 AN: 3088

European-Finnish (FIN) AF: 0.217 AC: 1527 AN: 7048

Middle Eastern (MID) AF: 0.222 AC: 40 AN: 180

European-Non Finnish (NFE) AF: 0.234 AC: 12082 AN: 51526

Other (OTH) AF: 0.242 AC: 336 AN: 1390

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.114 Hom.: 5266

ExAC AF: 0.199 AC: 24116

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		-0.27
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
Mutation Taster		=100/0	polymorphism

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