6-32584361-G-C

Position:

• chr6-32584361-G-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BS1 BS2

The NM_002124.4(HLA-DRB1):​c.118C>G​(p.Pro40Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts 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 0.033 (119 hom., cov: 11)
  • Exomes 𝑓: 0.031 (4199 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-DRB1 NM_002124.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -10.4

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.

• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.033 (2489/75434) while in subpopulation NFE AF= 0.0412 (1354/32872). AF 95% confidence interval is 0.0394. There are 119 homozygotes in gnomad4. There are 1098 alleles in male gnomad4 subpopulation. Median coverage is 11. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 119 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HLA-DRB1	NM_002124.4	c.118C>G	p.Pro40Ala	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.118C>G	p.Pro40Ala	missense_variant	2/6	6	NM_002124.4	ENSP00000353099.5

Frequencies

GnomAD3 genomes AF: 0.0330 AC: 2490 AN: 75346 Hom.: 121 Cov.: 11

Gnomad AFR AF: 0.0194

Gnomad AMI AF: 0.0764

Gnomad AMR AF: 0.0411

Gnomad ASJ AF: 0.0517

Gnomad EAS AF: 0.0322

Gnomad SAS AF: 0.0233

Gnomad FIN AF: 0.0266

Gnomad MID AF: 0.0287

Gnomad NFE AF: 0.0412

Gnomad OTH AF: 0.0243

GnomAD3 exomes AF: 0.00590 AC: 380 AN: 64458 Hom.: 27 AF XY: 0.00593 AC XY: 212 AN XY: 35728

Gnomad AFR exome AF: 0.00194

Gnomad AMR exome AF: 0.0125

Gnomad ASJ exome AF: 0.00844

Gnomad EAS exome AF: 0.00455

Gnomad SAS exome AF: 0.00456

Gnomad FIN exome AF: 0.00427

Gnomad NFE exome AF: 0.00540

Gnomad OTH exome AF: 0.00513

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0314 AC: 21521 AN: 685612 Hom.: 4199 Cov.: 11 AF XY: 0.0323 AC XY: 11452 AN XY: 354962

Gnomad4 AFR exome AF: 0.0150

Gnomad4 AMR exome AF: 0.0533

Gnomad4 ASJ exome AF: 0.0417

Gnomad4 EAS exome AF: 0.0377

Gnomad4 SAS exome AF: 0.0495

Gnomad4 FIN exome AF: 0.0249

Gnomad4 NFE exome AF: 0.0278

Gnomad4 OTH exome AF: 0.0359

GnomAD4 genome AF: 0.0330 AC: 2489 AN: 75434 Hom.: 119 Cov.: 11 AF XY: 0.0302 AC XY: 1098 AN XY: 36390

Gnomad4 AFR AF: 0.0194

Gnomad4 AMR AF: 0.0409

Gnomad4 ASJ AF: 0.0517

Gnomad4 EAS AF: 0.0331

Gnomad4 SAS AF: 0.0224

Gnomad4 FIN AF: 0.0266

Gnomad4 NFE AF: 0.0412

Gnomad4 OTH AF: 0.0239

Alfa AF: 0.103 Hom.: 88

ExAC AF: 0.114 AC: 8811

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	0.0010
DANN	Benign	0.16
DEOGEN2	Benign	0.00065	T
Eigen	Benign	-3.1
Eigen_PC	Benign	-3.2
FATHMM_MKL	Benign	0.0013	N
LIST_S2	Benign	0.040	T
MetaRNN	Benign	0.0054	T
MetaSVM	Benign	-0.95	T
PROVEAN	Benign	1.8	N
REVEL	Benign	0.028
Sift	Benign	0.65	T
Sift4G	Benign	0.58	T
Polyphen		0.0	B
Vest4		0.057
MPC		0.69
ClinPred		0.0054	T
GERP RS		-7.0
Varity_R		0.10
gMVP		0.17

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.25		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs9269955; hg19: chr6-32552138;