rs1136881

Positions:

• chr6-32580855-T-A
• chr6-32580855-T-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_002124.4(HLA-DRB1):​c.654A>T​(p.Arg218Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.20 (264 hom., cov: 27)
  • Exomes 𝑓: 0.23 (1688 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-DRB1 NM_002124.4 missense, splice_region
• Scores: Splicing: ADA: 0.00004211
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.12

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0022968054).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HLA-DRB1	NM_002124.4	c.654A>T	p.Arg218Ser	missense_variant, splice_region_variant	4/6	ENST00000360004.6	NP_002115.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HLA-DRB1	ENST00000360004.6	c.654A>T	p.Arg218Ser	missense_variant, splice_region_variant	4/6	6	NM_002124.4	ENSP00000353099.5

Frequencies

GnomAD3 genomes AF: 0.00 AC: 27196 AN: 134824 Hom.: 263 Cov.: 27 FAILED QC

Gnomad AFR AF: 0.251

Gnomad AMI AF: 0.133

Gnomad AMR AF: 0.218

Gnomad ASJ AF: 0.243

Gnomad EAS AF: 0.219

Gnomad SAS AF: 0.224

Gnomad FIN AF: 0.163

Gnomad MID AF: 0.332

Gnomad NFE AF: 0.171

Gnomad OTH AF: 0.207

GnomAD3 exomes AF: 0.213 AC: 47745 AN: 223998 Hom.: 833 AF XY: 0.215 AC XY: 25944 AN XY: 120666

Gnomad AFR exome AF: 0.266

Gnomad AMR exome AF: 0.257

Gnomad ASJ exome AF: 0.256

Gnomad EAS exome AF: 0.257

Gnomad SAS exome AF: 0.275

Gnomad FIN exome AF: 0.175

Gnomad NFE exome AF: 0.172

Gnomad OTH exome AF: 0.209

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.233 AC: 272277 AN: 1170354 Hom.: 1688 Cov.: 70 AF XY: 0.234 AC XY: 137382 AN XY: 586122

Gnomad4 AFR exome AF: 0.282

Gnomad4 AMR exome AF: 0.278

Gnomad4 ASJ exome AF: 0.292

Gnomad4 EAS exome AF: 0.225

Gnomad4 SAS exome AF: 0.296

Gnomad4 FIN exome AF: 0.180

Gnomad4 NFE exome AF: 0.226

Gnomad4 OTH exome AF: 0.221

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.202 AC: 27232 AN: 134926 Hom.: 264 Cov.: 27 AF XY: 0.203 AC XY: 13321 AN XY: 65666

Gnomad4 AFR AF: 0.252

Gnomad4 AMR AF: 0.218

Gnomad4 ASJ AF: 0.243

Gnomad4 EAS AF: 0.218

Gnomad4 SAS AF: 0.225

Gnomad4 FIN AF: 0.163

Gnomad4 NFE AF: 0.171

Gnomad4 OTH AF: 0.208

Alfa AF: 0.224 Hom.: 39

ExAC AF: 0.226 AC: 27472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	18
DANN	Benign	0.95
DEOGEN2	Benign	0.033	T
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.51	T
MetaRNN	Benign	0.0023	T
MetaSVM	Benign	-0.94	T
PROVEAN	Uncertain	-3.3	D
REVEL	Benign	0.16
Sift	Benign	0.044	D
Sift4G	Benign	0.10	T
Polyphen		0.94	P
Vest4		0.14
MutPred		0.28		Gain of disorder (P = 0.0493);
MPC		0.85
ClinPred		0.029	T
GERP RS		1.0
Varity_R		0.73
gMVP		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000042
dbscSNV1_RF	Benign	0.0040
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: rs1136881; hg19: chr6-32548632; COSMIC: COSV63511425;