6-32584360-G-C

Variant names:

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

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.119C>G​(p.Pro40Arg) 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 0.0063 (2 hom., cov: 12)
  • Exomes 𝑓: 0.0095 (280 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007349521).
• BS2: High Homozygotes in GnomAd4 at 2 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.119C>G	p.Pro40Arg	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>G	p.Pro40Arg	missense	Exon 2 of 6	ENSP00000353099.5
	HLA-DRB1	ENST00000696610.1		n.*24C>G		non_coding_transcript_exon	Exon 3 of 7	ENSP00000512754.1
	HLA-DRB1	ENST00000696611.1		n.42C>G		non_coding_transcript_exon	Exon 2 of 6

Frequencies

GnomAD3 genomes AF: 0.00636 AC: 529 AN: 83206 Hom.: 2 Cov.: 12

Gnomad AFR AF: 0.00472

Gnomad AMI AF: 0.0185

Gnomad AMR AF: 0.00677

Gnomad ASJ AF: 0.00624

Gnomad EAS AF: 0.00253

Gnomad SAS AF: 0.00523

Gnomad FIN AF: 0.00308

Gnomad MID AF: 0.00500

Gnomad NFE AF: 0.00815

Gnomad OTH AF: 0.00477

GnomAD2 exomes AF: 0.000574 AC: 43 AN: 74940 AF XY: 0.000311

Gnomad AFR exome AF: 0.000485

Gnomad AMR exome AF: 0.000895

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000729

Gnomad NFE exome AF: 0.000819

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00948 AC: 6498 AN: 685524 Hom.: 280 Cov.: 10 AF XY: 0.0101 AC XY: 3604 AN XY: 355112

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

African (AFR) AF: 0.00748 AC: 148 AN: 19790

American (AMR) AF: 0.0127 AC: 349 AN: 27588

Ashkenazi Jewish (ASJ) AF: 0.0131 AC: 210 AN: 16090

East Asian (EAS) AF: 0.00246 AC: 64 AN: 25974

South Asian (SAS) AF: 0.0121 AC: 734 AN: 60444

European-Finnish (FIN) AF: 0.00781 AC: 277 AN: 35478

Middle Eastern (MID) AF: 0.0358 AC: 129 AN: 3604

European-Non Finnish (NFE) AF: 0.00914 AC: 4243 AN: 464176

Other (OTH) AF: 0.0106 AC: 344 AN: 32380

⚠️ 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 AF: 0.00633 AC: 527 AN: 83308 Hom.: 2 Cov.: 12 AF XY: 0.00567 AC XY: 228 AN XY: 40188

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

African (AFR) AF: 0.00471 AC: 117 AN: 24854

American (AMR) AF: 0.00675 AC: 50 AN: 7406

Ashkenazi Jewish (ASJ) AF: 0.00624 AC: 13 AN: 2082

East Asian (EAS) AF: 0.00253 AC: 7 AN: 2762

South Asian (SAS) AF: 0.00483 AC: 12 AN: 2484

European-Finnish (FIN) AF: 0.00308 AC: 17 AN: 5528

Middle Eastern (MID) AF: 0.00510 AC: 1 AN: 196

European-Non Finnish (NFE) AF: 0.00812 AC: 296 AN: 36442

Other (OTH) AF: 0.00468 AC: 5 AN: 1068

⚠️ 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: 0.00 Hom.: 0

ExAC AF: 0.00208 AC: 172

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.0010
DANN	Benign	0.16
DEOGEN2	Benign	0.00086	T
Eigen	Benign	-3.2
Eigen_PC	Benign	-3.3
FATHMM_MKL	Benign	0.0018	N
LIST_S2	Benign	0.035	T
MetaRNN	Benign	0.0073	T
MetaSVM	Benign	-0.83	T
PhyloP100		-15
PROVEAN	Benign	0.080	N
REVEL	Benign	0.033
Sift	Benign	0.37	T
Sift4G	Benign	0.37	T
Polyphen		0.44	B
Vest4		0.088
MVP		0.085
MPC		0.76
ClinPred		0.013	T
GERP RS		-7.0
Varity_R		0.13
gMVP		0.41
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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;