6-32584314-G-C

Variant names:

• chr6-32584314-G-C
• rs1059572
• NM_002124.4:c.165C>G

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.165C>G​(p.Phe55Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.103 in 1,301,238 control chromosomes in the GnomAD database, including 17,297 homozygotes. 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.099 (1457 hom., cov: 20)
  • Exomes 𝑓: 0.10 (15840 hom.)
• Consequence: HLA-DRB1 NM_002124.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.12
• Publications: 15 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=0.022254556).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.114 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLA-DRB1	NM_002124.4	MANE Select	c.165C>G	p.Phe55Leu	missense	Exon 2 of 6	NP_002115.2	P01911

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLA-DRB1	ENST00000360004.6	TSL:6 MANE Select	c.165C>G	p.Phe55Leu	missense	Exon 2 of 6	ENSP00000353099.5	P01911
	HLA-DRB1	ENST00000963203.1		c.243C>G	p.Phe81Leu	missense	Exon 2 of 6	ENSP00000633262.1
	HLA-DRB1	ENST00000859900.1		c.165C>G	p.Phe55Leu	missense	Exon 2 of 5	ENSP00000529959.1

Frequencies

GnomAD3 genomes AF: 0.0994 AC: 12864 AN: 129470 Hom.: 1456 Cov.: 20

Gnomad AFR AF: 0.0643

Gnomad AMI AF: 0.218

Gnomad AMR AF: 0.0899

Gnomad ASJ AF: 0.134

Gnomad EAS AF: 0.0164

Gnomad SAS AF: 0.0331

Gnomad FIN AF: 0.201

Gnomad MID AF: 0.0417

Gnomad NFE AF: 0.116

Gnomad OTH AF: 0.0949

GnomAD2 exomes AF: 0.0107 AC: 1820 AN: 170260 AF XY: 0.00957

Gnomad AFR exome AF: 0.00908

Gnomad AMR exome AF: 0.0143

Gnomad ASJ exome AF: 0.00635

Gnomad EAS exome AF: 0.00234

Gnomad FIN exome AF: 0.0192

Gnomad NFE exome AF: 0.0118

Gnomad OTH exome AF: 0.00908

GnomAD4 exome AF: 0.104 AC: 121430 AN: 1171666 Hom.: 15840 Cov.: 31 AF XY: 0.101 AC XY: 60026 AN XY: 592338

African (AFR) AF: 0.0562 AC: 1677 AN: 29824

American (AMR) AF: 0.0743 AC: 3201 AN: 43074

Ashkenazi Jewish (ASJ) AF: 0.119 AC: 2839 AN: 23856

East Asian (EAS) AF: 0.0407 AC: 1515 AN: 37240

South Asian (SAS) AF: 0.0296 AC: 2396 AN: 80950

European-Finnish (FIN) AF: 0.203 AC: 9841 AN: 48450

Middle Eastern (MID) AF: 0.0404 AC: 217 AN: 5366

European-Non Finnish (NFE) AF: 0.111 AC: 94867 AN: 852282

Other (OTH) AF: 0.0963 AC: 4877 AN: 50624

GnomAD4 genome AF: 0.0994 AC: 12874 AN: 129572 Hom.: 1457 Cov.: 20 AF XY: 0.0996 AC XY: 6243 AN XY: 62666

African (AFR) AF: 0.0643 AC: 2296 AN: 35732

American (AMR) AF: 0.0898 AC: 1181 AN: 13156

Ashkenazi Jewish (ASJ) AF: 0.134 AC: 418 AN: 3120

East Asian (EAS) AF: 0.0162 AC: 67 AN: 4136

South Asian (SAS) AF: 0.0344 AC: 136 AN: 3958

European-Finnish (FIN) AF: 0.201 AC: 1634 AN: 8144

Middle Eastern (MID) AF: 0.0485 AC: 13 AN: 268

European-Non Finnish (NFE) AF: 0.116 AC: 6796 AN: 58552

Other (OTH) AF: 0.0937 AC: 161 AN: 1718

Alfa AF: 0.0531 Hom.: 229

ExAC AF: 0.0443 AC: 5130

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	0.77
DANN	Benign	0.32
DEOGEN2	Benign	0.020	T
Eigen	Benign	-2.2
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.13	T
MetaRNN	Benign	0.022	T
MetaSVM	Benign	-1.1	T
PhyloP100		-2.1
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.38
Sift	Benign	0.31	T
Sift4G	Benign	0.45	T
Polyphen		0.0030	B
Vest4		0.029
MutPred		0.15		Loss of sheet (P = 0.1501)
MPC		0.84
ClinPred		0.012	T
GERP RS		-6.6
Varity_R		0.42
gMVP		0.41
Mutation Taster		=100/0	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: rs1059572; hg19: chr6-32552091; COSMIC: COSV63513006;