chr6-32584361-G-C

Variant names:

• chr6-32584361-G-C
• rs9269955
• NM_002124.4:c.118C>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. 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. 12/21 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 0.033 (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
• 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High Homozygotes in GnomAd4 at 119 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.118C>G	p.Pro40Ala	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.118C>G	p.Pro40Ala	missense	Exon 2 of 6	ENSP00000353099.5
	HLA-DRB1	ENST00000696610.1		n.*23C>G		non_coding_transcript_exon	Exon 3 of 7	ENSP00000512754.1
	HLA-DRB1	ENST00000696611.1		n.41C>G		non_coding_transcript_exon	Exon 2 of 6

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

GnomAD2 exomes AF: 0.00590 AC: 380 AN: 64458 AF XY: 0.00593

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 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

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

African (AFR) AF: 0.0150 AC: 286 AN: 19020

American (AMR) AF: 0.0533 AC: 1471 AN: 27588

Ashkenazi Jewish (ASJ) AF: 0.0417 AC: 669 AN: 16060

East Asian (EAS) AF: 0.0377 AC: 980 AN: 25978

South Asian (SAS) AF: 0.0495 AC: 2926 AN: 59054

European-Finnish (FIN) AF: 0.0249 AC: 890 AN: 35746

Middle Eastern (MID) AF: 0.0468 AC: 171 AN: 3650

European-Non Finnish (NFE) AF: 0.0278 AC: 12953 AN: 465796

Other (OTH) AF: 0.0359 AC: 1175 AN: 32720

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

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

African (AFR) AF: 0.0194 AC: 446 AN: 23020

American (AMR) AF: 0.0409 AC: 273 AN: 6668

Ashkenazi Jewish (ASJ) AF: 0.0517 AC: 101 AN: 1952

East Asian (EAS) AF: 0.0331 AC: 79 AN: 2384

South Asian (SAS) AF: 0.0224 AC: 48 AN: 2144

European-Finnish (FIN) AF: 0.0266 AC: 129 AN: 4852

Middle Eastern (MID) AF: 0.0291 AC: 5 AN: 172

European-Non Finnish (NFE) AF: 0.0412 AC: 1354 AN: 32872

Other (OTH) AF: 0.0239 AC: 23 AN: 964

⚠️ 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: 0.103 Hom.: 88

ExAC AF: 0.114 AC: 8811

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		-10
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
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs9269955; hg19: chr6-32552138;