Genetic Variant NM_002124.4:c.118C>T (chr6-32584361-G-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_002124.4(HLA-DRB1):c.118C>T(p.Pro40Ser) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000089 ( 0 hom., cov: 11)

Exomes 𝑓: 0.00023 ( 2 hom. )

Failed GnomAD Quality Control

Consequence

HLA-DRB1
NM_002124.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -10.4

Publications

21 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: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009984314).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-DRB1	NM_002124.4 link	c.118C>T	p.Pro40Ser	missense_variant	Exon 2 of 6	ENST00000360004.6	NP_002115.2	P01911D7RIH8A0A224MM52X5DNQ0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLA-DRB1	ENST00000360004.6 link	c.118C>T	p.Pro40Ser	missense_variant	Exon 2 of 6	6	NM_002124.4	ENSP00000353099.5		P01911

Frequencies

GnomAD3 genomes

AF:

0.0000892

AC:

AN:

78482

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000852

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000435

Gnomad ASJ

AF:

0.000497

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000288

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000465

AC:

AN:

64458

AF XY:

0.0000560

show subpopulations

Gnomad AFR exome

AF:

0.000277

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000569

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000230

AC:

164

AN:

713888

Hom.:

Cov.:

AF XY:

0.000222

AC XY:

AN XY:

369898

show subpopulations

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

African (AFR)

AF:

0.000409

AC:

AN:

19562

American (AMR)

AF:

0.000441

AC:

AN:

29454

Ashkenazi Jewish (ASJ)

AF:

0.000415

AC:

AN:

16884

East Asian (EAS)

AF:

0.000399

AC:

AN:

27570

South Asian (SAS)

AF:

0.000224

AC:

AN:

62464

European-Finnish (FIN)

AF:

0.000161

AC:

AN:

37266

Middle Eastern (MID)

AF:

0.000262

AC:

AN:

3816

European-Non Finnish (NFE)

AF:

0.000189

AC:

AN:

482640

Other (OTH)

AF:

0.000380

AC:

AN:

34232

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.311

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000891

AC:

AN:

78572

Hom.:

Cov.:

AF XY:

0.0000793

AC XY:

AN XY:

37848

show subpopulations

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

African (AFR)

AF:

0.0000849

AC:

AN:

23548

American (AMR)

AF:

0.000434

AC:

AN:

6918

Ashkenazi Jewish (ASJ)

AF:

0.000497

AC:

AN:

2012

East Asian (EAS)

AF:

0.00

AC:

AN:

2488

South Asian (SAS)

AF:

0.00

AC:

AN:

2224

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5006

Middle Eastern (MID)

AF:

0.00

AC:

AN:

178

European-Non Finnish (NFE)

AF:

0.0000288

AC:

AN:

34758

Other (OTH)

AF:

0.00

AC:

AN:

996

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0000000000686732), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.296

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00

Hom.:

ExAC

AF:

0.00475

AC:

368

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.72

CADD

Benign

0.0010

(source)

DANN

Benign

0.17

DEOGEN2

Benign

0.00065

Eigen

Benign

-2.9

Eigen_PC

Benign

-3.1

FATHMM_MKL

Benign

0.0016

LIST_S2

Benign

0.045

MetaRNN

Benign

0.010

MetaSVM

Benign

-0.95

PhyloP100

-10

PROVEAN

Benign

1.5

REVEL

Benign

0.034

Sift

Benign

0.58

Sift4G

Benign

0.42

Polyphen

0.0

Vest4

0.12

MVP

0.040

MPC

0.72

ClinPred

0.022

GERP RS

-7.0

Varity_R

0.092

gMVP

0.28

Mutation Taster

=100/0

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over