rs17878703

Variant names:

• chr6-32584360-G-A
• rs17878703
• NM_002124.4:c.119C>T

Your query was ambiguous. Multiple possible variants found:

• chr6-32584360-G-A
• chr6-32584360-G-C
• chr6-32584360-G-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002124.4(HLA-DRB1):​c.119C>T​(p.Pro40Leu) 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 0.35 (3858 hom., cov: 12)
  • Exomes 𝑓: 0.19 (16204 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-DRB1 NM_002124.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -14.8
• Publications: 21 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.866323E-4).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.349 is higher than 0.05.

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.119C>T	p.Pro40Leu	missense	Exon 2 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.119C>T	p.Pro40Leu	missense	Exon 2 of 6	ENSP00000353099.5
	HLA-DRB1	ENST00000696610.1		n.*24C>T		non_coding_transcript_exon	Exon 3 of 7	ENSP00000512754.1
	HLA-DRB1	ENST00000696611.1		n.42C>T		non_coding_transcript_exon	Exon 2 of 6

Frequencies

GnomAD3 genomes AF: 0.349 AC: 28690 AN: 82302 Hom.: 3855 Cov.: 12

Gnomad AFR AF: 0.333

Gnomad AMI AF: 0.504

Gnomad AMR AF: 0.338

Gnomad ASJ AF: 0.427

Gnomad EAS AF: 0.306

Gnomad SAS AF: 0.289

Gnomad FIN AF: 0.394

Gnomad MID AF: 0.378

Gnomad NFE AF: 0.354

Gnomad OTH AF: 0.373

GnomAD2 exomes AF: 0.0263 AC: 1974 AN: 74940 AF XY: 0.0259

Gnomad AFR exome AF: 0.0235

Gnomad AMR exome AF: 0.0265

Gnomad ASJ exome AF: 0.0542

Gnomad EAS exome AF: 0.0220

Gnomad FIN exome AF: 0.0303

Gnomad NFE exome AF: 0.0256

Gnomad OTH exome AF: 0.0415

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.189 AC: 124871 AN: 660150 Hom.: 16204 Cov.: 10 AF XY: 0.197 AC XY: 67254 AN XY: 341222

African (AFR) AF: 0.190 AC: 3546 AN: 18652

American (AMR) AF: 0.179 AC: 4757 AN: 26580

Ashkenazi Jewish (ASJ) AF: 0.298 AC: 4588 AN: 15386

East Asian (EAS) AF: 0.234 AC: 5814 AN: 24846

South Asian (SAS) AF: 0.226 AC: 12731 AN: 56288

European-Finnish (FIN) AF: 0.310 AC: 10739 AN: 34660

Middle Eastern (MID) AF: 0.263 AC: 914 AN: 3480

European-Non Finnish (NFE) AF: 0.167 AC: 75067 AN: 449032

Other (OTH) AF: 0.215 AC: 6715 AN: 31226

GnomAD4 genome AF: 0.349 AC: 28723 AN: 82394 Hom.: 3858 Cov.: 12 AF XY: 0.347 AC XY: 13804 AN XY: 39730

African (AFR) AF: 0.333 AC: 8067 AN: 24198

American (AMR) AF: 0.337 AC: 2451 AN: 7266

Ashkenazi Jewish (ASJ) AF: 0.427 AC: 880 AN: 2060

East Asian (EAS) AF: 0.306 AC: 818 AN: 2676

South Asian (SAS) AF: 0.291 AC: 699 AN: 2400

European-Finnish (FIN) AF: 0.394 AC: 2172 AN: 5512

Middle Eastern (MID) AF: 0.386 AC: 71 AN: 184

European-Non Finnish (NFE) AF: 0.354 AC: 12928 AN: 36546

Other (OTH) AF: 0.367 AC: 388 AN: 1058

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0488 AC: 4026

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.0010
DANN	Benign	0.22
DEOGEN2	Benign	0.00065	T
Eigen	Benign	-3.4
Eigen_PC	Benign	-3.5
FATHMM_MKL	Benign	0.00087	N
LIST_S2	Benign	0.021	T
MetaRNN	Benign	0.00079	T
MetaSVM	Benign	-0.84	T
PhyloP100		-15
PROVEAN	Benign	0.91	N
REVEL	Benign	0.029
Sift	Benign	0.67	T
Sift4G	Benign	0.66	T
Polyphen		0.0010	B
Vest4		0.045
MPC		0.73
ClinPred		0.0045	T
GERP RS		-7.0
Varity_R		0.090
gMVP		0.32
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs17878703; hg19: chr6-32552137; COSMIC: COSV63512628;