6-32584282-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_002124.4(HLA-DRB1):c.197C>A(p.Ser66Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S66F) has been classified as Benign.

Frequency

Genomes: 𝑓 0.58 ( 18334 hom., cov: 17)

Exomes 𝑓: 0.55 ( 185262 hom. )

Failed GnomAD Quality Control

Consequence

HLA-DRB1
NM_002124.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -6.35

Publications

28 publications found

Variant links:

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

HLA-DRB1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=2.5418816E-5).

BP6

Variant 6-32584282-G-T is Benign according to our data. Variant chr6-32584282-G-T is described in ClinVar as Benign. ClinVar VariationId is 1260112.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.654 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.197C>A	p.Ser66Tyr	missense	Exon 2 of 6	NP_002115.2	P01911

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HLA-DRB1	ENST00000360004.6	TSL:6 MANE Select	c.197C>A	p.Ser66Tyr	missense	Exon 2 of 6	ENSP00000353099.5	P01911
HLA-DRB1	ENST00000963203.1		c.275C>A	p.Ser92Tyr	missense	Exon 2 of 6	ENSP00000633262.1
HLA-DRB1	ENST00000859900.1		c.197C>A	p.Ser66Tyr	missense	Exon 2 of 5	ENSP00000529959.1

Frequencies

GnomAD3 genomes

AF:

0.579

AC:

65401

AN:

112994

Hom.:

18317

Cov.:

show subpopulations

Gnomad AFR

AF:

0.572

Gnomad AMI

AF:

0.538

Gnomad AMR

AF:

0.666

Gnomad ASJ

AF:

0.661

Gnomad EAS

AF:

0.539

Gnomad SAS

AF:

0.474

Gnomad FIN

AF:

0.515

Gnomad MID

AF:

0.756

Gnomad NFE

AF:

0.577

Gnomad OTH

AF:

0.605

GnomAD2 exomes

AF:

0.568

AC:

87771

AN:

154416

AF XY:

0.570

show subpopulations

Gnomad AFR exome

AF:

0.548

Gnomad AMR exome

AF:

0.672

Gnomad ASJ exome

AF:

0.684

Gnomad EAS exome

AF:

0.443

Gnomad FIN exome

AF:

0.541

Gnomad NFE exome

AF:

0.571

Gnomad OTH exome

AF:

0.531

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.553

AC:

630509

AN:

1140416

Hom.:

185262

Cov.:

AF XY:

0.555

AC XY:

318346

AN XY:

573406

show subpopulations

African (AFR)

AF:

0.585

AC:

16402

AN:

28014

American (AMR)

AF:

0.726

AC:

29044

AN:

39988

Ashkenazi Jewish (ASJ)

AF:

0.653

AC:

15697

AN:

24024

East Asian (EAS)

AF:

0.570

AC:

19714

AN:

34560

South Asian (SAS)

AF:

0.559

AC:

40171

AN:

71824

European-Finnish (FIN)

AF:

0.545

AC:

24730

AN:

45368

Middle Eastern (MID)

AF:

0.655

AC:

3307

AN:

5052

European-Non Finnish (NFE)

AF:

0.539

AC:

454688

AN:

842962

Other (OTH)

AF:

0.550

AC:

26756

AN:

48624

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.524

Heterozygous variant carriers

5808

11617

17425

23234

29042

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11448

22896

34344

45792

57240

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.579

AC:

65465

AN:

113086

Hom.:

18334

Cov.:

AF XY:

0.576

AC XY:

31347

AN XY:

54454

show subpopulations

African (AFR)

AF:

0.572

AC:

17019

AN:

29772

American (AMR)

AF:

0.667

AC:

7492

AN:

11234

Ashkenazi Jewish (ASJ)

AF:

0.661

AC:

1949

AN:

2950

East Asian (EAS)

AF:

0.540

AC:

2124

AN:

3930

South Asian (SAS)

AF:

0.474

AC:

1497

AN:

3156

European-Finnish (FIN)

AF:

0.515

AC:

3674

AN:

7130

Middle Eastern (MID)

AF:

0.742

AC:

175

AN:

236

European-Non Finnish (NFE)

AF:

0.577

AC:

30267

AN:

52496

Other (OTH)

AF:

0.603

AC:

875

AN:

1452

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

678

1357

2035

2714

3392

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

552

1104

1656

2208

2760

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.449

Hom.:

633

ESP6500AA

AF:

0.715

AC:

3132

ESP6500EA

AF:

0.685

AC:

5870

ExAC

AF:

0.604

AC:

72865

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.057

BayesDel_addAF

Benign

-0.78

BayesDel_noAF

Benign

-0.75

CADD

Benign

0.0010

(source)

DANN

Benign

0.089

DEOGEN2

Benign

0.0065

Eigen

Benign

-4.0

Eigen_PC

Benign

-4.0

FATHMM_MKL

Benign

0.00079

LIST_S2

Benign

0.0065

MetaRNN

Benign

0.000025

MetaSVM

Benign

-0.90

PhyloP100

-6.4

PROVEAN

Benign

3.8

REVEL

Benign

0.070

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.16

Vest4

0.065

MPC

0.92

ClinPred

0.015

GERP RS

-7.0

Varity_R

0.15

gMVP

0.27

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over