dbSNP rs2308910: HLA-DPA1:p.Glu59Asp (chr6-33069810-T-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_033554.4(HLA-DPA1):c.177A>T(p.Glu59Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00132 in 1,610,924 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.0036 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 34 hom. )

Consequence

HLA-DPA1
NM_033554.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -3.12

Variant links:

Genes affected

HLA-DPA1 (HGNC:4938): (major histocompatibility complex, class II, DP alpha 1) HLA-DPA1 belongs to the HLA class II alpha chain paralogues. This class II molecule is a heterodimer consisting of an alpha (DPA) and a beta (DPB) 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 (APC: B lymphocytes, dendritic cells, macrophages). The alpha chain is approximately 33-35 kDa and its gene contains 5 exons. Exon one encodes the leader peptide, exons 2 and 3 encode the two extracellular domains, exon 4 encodes the transmembrane domain and the cytoplasmic tail. Within the DP molecule both the alpha chain and the beta chain contain the polymorphisms specifying the peptide binding specificities, resulting in up to 4 different molecules. [provided by RefSeq, Jul 2008]

HLA-DPA1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003968984).

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00356 (543/152324) while in subpopulation EAS AF= 0.0256 (133/5186). AF 95% confidence interval is 0.0221. There are 3 homozygotes in gnomad4. There are 281 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	Protein
HLA-DPA1	NM_001242524.2 link	c.177A>T	p.Glu59Asp	missense_variant	Exon 3 of 6	NP_001229453.1
HLA-DPA1	NM_001242525.2 link	c.177A>T	p.Glu59Asp	missense_variant	Exon 3 of 6	NP_001229454.1
HLA-DPA1	NM_001405020.1 link	c.177A>T	p.Glu59Asp	missense_variant	Exon 2 of 4	NP_001391949.1
HLA-DPA1	NM_033554.4 link	c.177A>T	p.Glu59Asp	missense_variant	Exon 2 of 5	NP_291032.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLA-DPA1	ENST00000692443.1 link	c.177A>T	p.Glu59Asp	missense_variant	Exon 2 of 5			ENSP00000509163.1		P20036

Frequencies

GnomAD3 genomes

AF:

0.00355

AC:

540

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00830

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000916

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0258

Gnomad SAS

AF:

0.00807

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00336

GnomAD3 exomes

AF:

0.00347

AC:

856

AN:

246558

Hom.:

AF XY:

0.00353

AC XY:

474

AN XY:

134412

show subpopulations

Gnomad AFR exome

AF:

0.00795

Gnomad AMR exome

AF:

0.000812

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0269

Gnomad SAS exome

AF:

0.00652

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000542

Gnomad OTH exome

AF:

0.00197

GnomAD4 exome

AF:

0.00108

AC:

1578

AN:

1458600

Hom.:

Cov.:

AF XY:

0.00127

AC XY:

920

AN XY:

725770

show subpopulations

Gnomad4 AFR exome

AF:

0.00721

Gnomad4 AMR exome

AF:

0.000872

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0125

Gnomad4 SAS exome

AF:

0.00626

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000243

Gnomad4 OTH exome

AF:

0.00390

GnomAD4 genome

AF:

0.00356

AC:

543

AN:

152324

Hom.:

Cov.:

AF XY:

0.00377

AC XY:

281

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.00835

Gnomad4 AMR

AF:

0.000915

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0256

Gnomad4 SAS

AF:

0.00807

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00380

Alfa

AF:

0.000196

Hom.:

Bravo

AF:

0.00390

ExAC

AF:

0.00319

AC:

375

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.57

CADD

Benign

1.2

DANN

Benign

0.97

DEOGEN2

Benign

0.0033

T;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.047

MetaRNN

Benign

0.0040

T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.4

L;.

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.25

N;N

REVEL

Benign

0.060

Sift

Uncertain

0.026

D;D

Sift4G

Uncertain

0.060

T;.

Polyphen

0.0

B;.

Vest4

0.16

MVP

0.014

MPC

0.43

ClinPred

0.0069

GERP RS

-5.1

Varity_R

0.22

gMVP

0.62

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over