rs9269743

Variant names:

• chr6-32580214-G-A
• rs9269743
• NM_002124.4:c.787+33C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_002124.4(HLA-DRB1):​c.787+33C>T variant causes a intron 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.

• Frequency:
  • Genomes: 𝑓 0.46 (11078 hom., cov: 11)
  • Exomes 𝑓: 0.43 (96143 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-DRB1 NM_002124.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0320
• Publications: 3 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BS2: High Homozygotes in GnomAd4 at 11078 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.787+33C>T		intron	N/A	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.787+33C>T		intron	N/A	ENSP00000353099.5	P01911
	HLA-DRB1	ENST00000963203.1		c.865+33C>T		intron	N/A	ENSP00000633262.1
	HLA-DRB1	ENST00000859900.1		c.763+532C>T		intron	N/A	ENSP00000529959.1

Frequencies

GnomAD3 genomes AF: 0.459 AC: 32873 AN: 71596 Hom.: 11062 Cov.: 11

Gnomad AFR AF: 0.553

Gnomad AMI AF: 0.289

Gnomad AMR AF: 0.430

Gnomad ASJ AF: 0.513

Gnomad EAS AF: 0.465

Gnomad SAS AF: 0.347

Gnomad FIN AF: 0.338

Gnomad MID AF: 0.598

Gnomad NFE AF: 0.434

Gnomad OTH AF: 0.519

GnomAD2 exomes AF: 0.560 AC: 85448 AN: 152482 AF XY: 0.568

Gnomad AFR exome AF: 0.669

Gnomad AMR exome AF: 0.513

Gnomad ASJ exome AF: 0.651

Gnomad EAS exome AF: 0.644

Gnomad FIN exome AF: 0.464

Gnomad NFE exome AF: 0.542

Gnomad OTH exome AF: 0.552

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.426 AC: 268140 AN: 629768 Hom.: 96143 Cov.: 10 AF XY: 0.443 AC XY: 144794 AN XY: 326488

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

African (AFR) AF: 0.597 AC: 10053 AN: 16828

American (AMR) AF: 0.615 AC: 13831 AN: 22498

Ashkenazi Jewish (ASJ) AF: 0.579 AC: 7694 AN: 13290

East Asian (EAS) AF: 0.498 AC: 9570 AN: 19206

South Asian (SAS) AF: 0.602 AC: 29938 AN: 49748

European-Finnish (FIN) AF: 0.476 AC: 17516 AN: 36790

Middle Eastern (MID) AF: 0.623 AC: 1619 AN: 2598

European-Non Finnish (NFE) AF: 0.375 AC: 165443 AN: 440970

Other (OTH) AF: 0.448 AC: 12476 AN: 27840

⚠️ 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: 0.459 AC: 32913 AN: 71658 Hom.: 11078 Cov.: 11 AF XY: 0.455 AC XY: 15737 AN XY: 34574

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

African (AFR) AF: 0.554 AC: 10676 AN: 19276

American (AMR) AF: 0.430 AC: 2461 AN: 5728

Ashkenazi Jewish (ASJ) AF: 0.513 AC: 797 AN: 1554

East Asian (EAS) AF: 0.465 AC: 897 AN: 1930

South Asian (SAS) AF: 0.345 AC: 636 AN: 1844

European-Finnish (FIN) AF: 0.338 AC: 1726 AN: 5112

Middle Eastern (MID) AF: 0.580 AC: 58 AN: 100

European-Non Finnish (NFE) AF: 0.434 AC: 15078 AN: 34776

Other (OTH) AF: 0.517 AC: 447 AN: 864

⚠️ 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: 0.642 Hom.: 3977

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.1
DANN	Benign	0.18
PhyloP100		-0.032
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs9269743;

hg19: chr6-32547991;

COSMIC: COSV63515473;