chr6-32581763-C-T

Variant names:

• chr6-32581763-C-T
• rs1059351
• NM_002124.4:c.446G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6 BS2

The NM_002124.4(HLA-DRB1):​c.446G>A​(p.Ser149Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.158 in 1,160,604 control chromosomes in the GnomAD database, including 79 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.18 (0 hom., cov: 23)
  • Exomes 𝑓: 0.16 (79 hom.)
• Consequence: HLA-DRB1 NM_002124.4 missense
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -1.59
• Publications: 13 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 -5 ACMG points.

• BP6: Variant 6-32581763-C-T is Benign according to our data. Variant chr6-32581763-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3060198.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High Homozygotes in GnomAdExome4 at 79 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLA-DRB1	NM_002124.4	MANE Select	c.446G>A	p.Ser149Asn	missense	Exon 3 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.446G>A	p.Ser149Asn	missense	Exon 3 of 6	ENSP00000353099.5	P01911
	HLA-DRB1	ENST00000963203.1		c.524G>A	p.Ser175Asn	missense	Exon 3 of 6	ENSP00000633262.1
	HLA-DRB1	ENST00000859900.1		c.446G>A	p.Ser149Asn	missense	Exon 3 of 5	ENSP00000529959.1

Frequencies

GnomAD3 genomes AF: 0.184 AC: 22612 AN: 122866 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.119

Gnomad AMI AF: 0.271

Gnomad AMR AF: 0.236

Gnomad ASJ AF: 0.225

Gnomad EAS AF: 0.262

Gnomad SAS AF: 0.192

Gnomad FIN AF: 0.186

Gnomad MID AF: 0.191

Gnomad NFE AF: 0.200

Gnomad OTH AF: 0.187

GnomAD2 exomes AF: 0.162 AC: 30792 AN: 190374 AF XY: 0.158

Gnomad AFR exome AF: 0.0852

Gnomad AMR exome AF: 0.210

Gnomad ASJ exome AF: 0.171

Gnomad EAS exome AF: 0.214

Gnomad FIN exome AF: 0.160

Gnomad NFE exome AF: 0.154

Gnomad OTH exome AF: 0.164

GnomAD4 exome AF: 0.155 AC: 161026 AN: 1037648 Hom.: 79 Cov.: 42 AF XY: 0.151 AC XY: 78686 AN XY: 519762

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

African (AFR) AF: 0.0720 AC: 1853 AN: 25722

American (AMR) AF: 0.169 AC: 5234 AN: 30894

Ashkenazi Jewish (ASJ) AF: 0.174 AC: 3425 AN: 19698

East Asian (EAS) AF: 0.252 AC: 7956 AN: 31588

South Asian (SAS) AF: 0.123 AC: 8128 AN: 66274

European-Finnish (FIN) AF: 0.167 AC: 7733 AN: 46204

Middle Eastern (MID) AF: 0.185 AC: 855 AN: 4632

European-Non Finnish (NFE) AF: 0.155 AC: 118782 AN: 768046

Other (OTH) AF: 0.158 AC: 7060 AN: 44590

⚠️ 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: 0.184 AC: 22624 AN: 122956 Hom.: 0 Cov.: 23 AF XY: 0.184 AC XY: 11004 AN XY: 59686

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

African (AFR) AF: 0.119 AC: 3830 AN: 32080

American (AMR) AF: 0.236 AC: 2839 AN: 12024

Ashkenazi Jewish (ASJ) AF: 0.225 AC: 668 AN: 2970

East Asian (EAS) AF: 0.263 AC: 1060 AN: 4034

South Asian (SAS) AF: 0.193 AC: 731 AN: 3792

European-Finnish (FIN) AF: 0.186 AC: 1561 AN: 8412

Middle Eastern (MID) AF: 0.179 AC: 44 AN: 246

European-Non Finnish (NFE) AF: 0.200 AC: 11364 AN: 56920

Other (OTH) AF: 0.186 AC: 315 AN: 1696

⚠️ 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: 0.197 Hom.: 7

ExAC AF: 0.188 AC: 22820

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	HLA-DRB1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	0.058
DANN	Benign	0.32
DEOGEN2	Benign	0.0088	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.038	N
LIST_S2	Benign	0.033	T
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-0.93	T
PhyloP100		-1.6
PROVEAN	Benign	-0.090	N
REVEL	Benign	0.020
Sift	Benign	1.0	T
Sift4G	Benign	0.32	T
Polyphen		0.0	B
Vest4		0.025
MPC		0.68
ClinPred		0.0020	T
GERP RS		0.026
Varity_R		0.13
gMVP		0.18
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.23		Position offset: -15

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

Other links and lift over

dbSNP: rs1059351; hg19: chr6-32549540; COSMIC: COSV63511185;