Genetic Variant HLA-DRB5:p.Pro126Pro (chr6-32519644-A-G) – ACMG Classification: Benign (-7 pts)

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_StrongBP6_ModerateBP7

The NM_002125.4(HLA-DRB5):c.378T>C(p.Pro126Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 0)

Exomes 𝑓: 0.0000017 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HLA-DRB5
NM_002125.4 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.21

Publications

0 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: Benign. The variant received -7 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.95).

BP6

Variant 6-32519644-A-G is Benign according to our data. Variant chr6-32519644-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 2656453.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-1.21 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-DRB5	NM_002125.4 link	c.378T>C	p.Pro126Pro	synonymous_variant	Exon 3 of 6	ENST00000374975.4	NP_002116.2	Q30154A0A2Z4LKS3
HLA-DRB5	XM_011514562.3 link	c.378T>C	p.Pro126Pro	synonymous_variant	Exon 3 of 6		XP_011512864.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLA-DRB5	ENST00000374975.4 link	c.378T>C	p.Pro126Pro	synonymous_variant	Exon 3 of 6	6	NM_002125.4	ENSP00000364114.3		Q30154
HLA-DRB5	ENST00000714490.1 link	c.371-83T>C		intron_variant	Intron 2 of 5			ENSP00000519744.1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

39688

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000169

AC:

AN:

593206

Hom.:

Cov.:

AF XY:

0.00000331

AC XY:

AN XY:

302442

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

12368

American (AMR)

AF:

0.00

AC:

AN:

19034

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

10860

East Asian (EAS)

AF:

0.00

AC:

AN:

24034

South Asian (SAS)

AF:

0.00

AC:

AN:

42206

European-Finnish (FIN)

AF:

0.00

AC:

AN:

29098

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2212

European-Non Finnish (NFE)

AF:

0.00000235

AC:

AN:

425728

Other (OTH)

AF:

0.00

AC:

AN:

27666

⚠️ 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: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

39688

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

19446

African (AFR)

AF:

0.00

AC:

AN:

10778

American (AMR)

AF:

0.00

AC:

AN:

3042

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

542

East Asian (EAS)

AF:

0.00

AC:

AN:

1464

South Asian (SAS)

AF:

0.00

AC:

AN:

1716

European-Finnish (FIN)

AF:

0.00

AC:

AN:

2514

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

18986

Other (OTH)

AF:

0.00

AC:

AN:

436

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

HLA-DRB5: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.95

CADD

Benign

0.64

(source)

DANN

Benign

0.53

PhyloP100

-1.2

Mutation Taster

=100/0

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

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

6-32519644-A-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over