6-32584360-G-A

Position:

• chr6-32584360-G-A

Variant summary

Our verdict is Benign. Variant got -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. 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. 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 0.35 (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

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 -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HLA-DRB1	NM_002124.4	c.119C>T	p.Pro40Leu	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>T	p.Pro40Leu	missense_variant	2/6	6	NM_002124.4	ENSP00000353099.5

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

GnomAD3 exomes AF: 0.0263 AC: 1974 AN: 74940 Hom.: 63 AF XY: 0.0259 AC XY: 1085 AN XY: 41846

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 SAS exome AF: 0.0201

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

Gnomad4 AFR exome AF: 0.190

Gnomad4 AMR exome AF: 0.179

Gnomad4 ASJ exome AF: 0.298

Gnomad4 EAS exome AF: 0.234

Gnomad4 SAS exome AF: 0.226

Gnomad4 FIN exome AF: 0.310

Gnomad4 NFE exome AF: 0.167

Gnomad4 OTH exome AF: 0.215

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

Gnomad4 AFR AF: 0.333

Gnomad4 AMR AF: 0.337

Gnomad4 ASJ AF: 0.427

Gnomad4 EAS AF: 0.306

Gnomad4 SAS AF: 0.291

Gnomad4 FIN AF: 0.394

Gnomad4 NFE AF: 0.354

Gnomad4 OTH AF: 0.367

ExAC AF: 0.0488 AC: 4026

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs17878703; hg19: chr6-32552137; COSMIC: COSV63512628;