6-32584360-G-C

Position:

• chr6-32584360-G-C

Variant summary

Our verdict is Benign. Variant got -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. 12/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P40D) has been classified as Likely benign.

• 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

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007349521).
• BS2: High Homozygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HLA-DRB1	NM_002124.4	c.119C>G	p.Pro40Arg	missense_variant	2/6	ENST00000360004.6	NP_002115.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HLA-DRB1	ENST00000360004.6	c.119C>G	p.Pro40Arg	missense_variant	2/6	6	NM_002124.4	ENSP00000353099.5

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

GnomAD3 exomes AF: 0.000574 AC: 43 AN: 74940 Hom.: 0 AF XY: 0.000311 AC XY: 13 AN XY: 41846

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 SAS exome AF: 0.000150

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

Gnomad4 AFR exome AF: 0.00748

Gnomad4 AMR exome AF: 0.0127

Gnomad4 ASJ exome AF: 0.0131

Gnomad4 EAS exome AF: 0.00246

Gnomad4 SAS exome AF: 0.0121

Gnomad4 FIN exome AF: 0.00781

Gnomad4 NFE exome AF: 0.00914

Gnomad4 OTH exome AF: 0.0106

GnomAD4 genome AF: 0.00633 AC: 527 AN: 83308 Hom.: 2 Cov.: 12 AF XY: 0.00567 AC XY: 228 AN XY: 40188

Gnomad4 AFR AF: 0.00471

Gnomad4 AMR AF: 0.00675

Gnomad4 ASJ AF: 0.00624

Gnomad4 EAS AF: 0.00253

Gnomad4 SAS AF: 0.00483

Gnomad4 FIN AF: 0.00308

Gnomad4 NFE AF: 0.00812

Gnomad4 OTH AF: 0.00468

ExAC AF: 0.00208 AC: 172

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs17878703; hg19: chr6-32552137;