dbSNP rs75457801: HLA-DRB5:p.Lys14Asn (chr6-32530183-C-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_002125.4(HLA-DRB5):c.42G>T(p.Lys14Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. K14K) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0047 ( 0 hom., cov: 23)

Exomes 𝑓: 0.00049 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HLA-DRB5
NM_002125.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.17

Publications

9 publications found

Variant links:

Genes affected

HLA-DRB5 (HGNC:4953): (major histocompatibility complex, class II, DR beta 5) HLA-DRB5 belongs to the HLA class II beta chain paralogues. This class II molecule is a heterodimer consisting of an alpha (DRA) and a beta (DRB) chain, 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 and its gene contains 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. Typing for these polymorphisms is routinely done for bone marrow and kidney transplantation. There are multiple pseudogenes of this gene. [provided by RefSeq, Feb 2020]

HLA-DRB5 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=0.015625268).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-DRB5	NM_002125.4 link	c.42G>T	p.Lys14Asn	missense_variant	Exon 1 of 6	ENST00000374975.4	NP_002116.2	Q30154A0A2Z4LKS3
HLA-DRB5	XM_011514562.3 link	c.42G>T	p.Lys14Asn	missense_variant	Exon 1 of 6		XP_011512864.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLA-DRB5	ENST00000374975.4 link	c.42G>T	p.Lys14Asn	missense_variant	Exon 1 of 6	6	NM_002125.4	ENSP00000364114.3		Q30154
HLA-DRB5	ENST00000714490.1 link	c.42G>T	p.Lys14Asn	missense_variant	Exon 1 of 6			ENSP00000519744.1

Frequencies

GnomAD3 genomes

AF:

0.00468

AC:

614

AN:

131286

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0101

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00347

Gnomad ASJ

AF:

0.00320

Gnomad EAS

AF:

0.00285

Gnomad SAS

AF:

0.00363

Gnomad FIN

AF:

0.00225

Gnomad MID

AF:

0.00667

Gnomad NFE

AF:

0.00251

Gnomad OTH

AF:

0.00550

GnomAD2 exomes

AF:

0.000552

AC:

AN:

148584

AF XY:

0.000482

show subpopulations

Gnomad AFR exome

AF:

0.00375

Gnomad AMR exome

AF:

0.000452

Gnomad ASJ exome

AF:

0.000496

Gnomad EAS exome

AF:

0.00154

Gnomad FIN exome

AF:

0.000209

Gnomad NFE exome

AF:

0.000231

Gnomad OTH exome

AF:

0.000560

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000490

AC:

572

AN:

1167200

Hom.:

Cov.:

AF XY:

0.000476

AC XY:

279

AN XY:

586710

show subpopulations

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

African (AFR)

AF:

0.00294

AC:

AN:

25548

American (AMR)

AF:

0.00107

AC:

AN:

39380

Ashkenazi Jewish (ASJ)

AF:

0.000690

AC:

AN:

21754

East Asian (EAS)

AF:

0.00111

AC:

AN:

34190

South Asian (SAS)

AF:

0.000986

AC:

AN:

75042

European-Finnish (FIN)

AF:

0.000500

AC:

AN:

41992

Middle Eastern (MID)

AF:

0.000829

AC:

AN:

4828

European-Non Finnish (NFE)

AF:

0.000306

AC:

268

AN:

875914

Other (OTH)

AF:

0.000721

AC:

AN:

48552

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.292

Heterozygous variant carriers

105

157

210

262

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00471

AC:

619

AN:

131404

Hom.:

Cov.:

AF XY:

0.00493

AC XY:

314

AN XY:

63666

show subpopulations

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

African (AFR)

AF:

0.0102

AC:

350

AN:

34364

American (AMR)

AF:

0.00346

AC:

AN:

13284

Ashkenazi Jewish (ASJ)

AF:

0.00320

AC:

AN:

3126

East Asian (EAS)

AF:

0.00286

AC:

AN:

4544

South Asian (SAS)

AF:

0.00364

AC:

AN:

4126

European-Finnish (FIN)

AF:

0.00225

AC:

AN:

8462

Middle Eastern (MID)

AF:

0.0108

AC:

AN:

278

European-Non Finnish (NFE)

AF:

0.00251

AC:

152

AN:

60598

Other (OTH)

AF:

0.00598

AC:

AN:

1838

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.315

Heterozygous variant carriers

121

161

201

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.00438

AC:

494

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.62

CADD

Benign

(source)

DANN

Benign

0.47

DEOGEN2

Benign

0.010

Eigen

Benign

-1.9

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.00099

LIST_S2

Uncertain

0.93

MetaRNN

Benign

0.016

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

PhyloP100

1.2

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.51

REVEL

Benign

0.067

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0040

Polyphen

0.0

Vest4

0.21

MutPred

0.20

Loss of ubiquitination at K14 (P = 0.027);

MVP

0.040

MPC

0.018

ClinPred

0.030

GERP RS

-3.0

PromoterAI

-0.021

Neutral

(source)

Varity_R

0.088

gMVP

0.24

Mutation Taster

=99/1

polymorphism

(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

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rs75457801

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