rs1136881

Variant names:

• chr6-32580855-T-A
• rs1136881
• NM_002124.4:c.654A>T

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Likely benign. The variant received -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. 14/21 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.

• 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
• Publications: 27 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: Likely_benign. The variant received -4 ACMG points.

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

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.654A>T	p.Arg218Ser	missense splice_region	Exon 4 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.654A>T	p.Arg218Ser	missense splice_region	Exon 4 of 6	ENSP00000353099.5
	HLA-DRB1	ENST00000696610.1		n.*559A>T		splice_region non_coding_transcript_exon	Exon 5 of 7	ENSP00000512754.1
	HLA-DRB1	ENST00000696611.1		n.577A>T		splice_region non_coding_transcript_exon	Exon 4 of 6

Frequencies

GnomAD3 genomes AF: 0.202 AC: 27196 AN: 134824 Hom.: 263 Cov.: 27

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

GnomAD2 exomes AF: 0.213 AC: 47745 AN: 223998 AF XY: 0.215

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 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

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

African (AFR) AF: 0.282 AC: 7938 AN: 28168

American (AMR) AF: 0.278 AC: 10696 AN: 38476

Ashkenazi Jewish (ASJ) AF: 0.292 AC: 6443 AN: 22066

East Asian (EAS) AF: 0.225 AC: 8184 AN: 36300

South Asian (SAS) AF: 0.296 AC: 21725 AN: 73374

European-Finnish (FIN) AF: 0.180 AC: 9046 AN: 50148

Middle Eastern (MID) AF: 0.279 AC: 1298 AN: 4652

European-Non Finnish (NFE) AF: 0.226 AC: 195973 AN: 867436

Other (OTH) AF: 0.221 AC: 10974 AN: 49734

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

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

African (AFR) AF: 0.252 AC: 9031 AN: 35904

American (AMR) AF: 0.218 AC: 2893 AN: 13276

Ashkenazi Jewish (ASJ) AF: 0.243 AC: 758 AN: 3124

East Asian (EAS) AF: 0.218 AC: 985 AN: 4514

South Asian (SAS) AF: 0.225 AC: 939 AN: 4180

European-Finnish (FIN) AF: 0.163 AC: 1530 AN: 9400

Middle Eastern (MID) AF: 0.332 AC: 91 AN: 274

European-Non Finnish (NFE) AF: 0.171 AC: 10513 AN: 61586

Other (OTH) AF: 0.208 AC: 381 AN: 1836

⚠️ 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: 0.224 Hom.: 39

ExAC AF: 0.226 AC: 27472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		-1.1
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
Mutation Taster		=91/9	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1136881; hg19: chr6-32548632; COSMIC: COSV63511425;