6-33068771-G-A

Position:

chr6-33068771-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_001242525.2(HLA-DPA1):c.662C>T(p.Thr221Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00731 in 1,612,986 control chromosomes in the GnomAD database, including 62 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T221A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0062 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0074 ( 60 hom. )

Consequence

HLA-DPA1
NM_001242525.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.0510

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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003586769).

BP6

Variant 6-33068771-G-A is Benign according to our data. Variant chr6-33068771-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 779334.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
HLA-DPA1	NM_033554.4 linkuse as main transcript	c.662C>T	p.Thr221Met	missense_variant	4/5	ENST00000692443.1	NP_291032.2
HLA-DPA1	NM_001242525.2 linkuse as main transcript	c.662C>T	p.Thr221Met	missense_variant	5/6		NP_001229454.1
HLA-DPA1	NM_001242524.2 linkuse as main transcript	c.662C>T	p.Thr221Met	missense_variant	5/6		NP_001229453.1
HLA-DPA1	NM_001405020.1 linkuse as main transcript	c.662C>T	p.Thr221Met	missense_variant	4/4		NP_001391949.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	Appris
HLA-DPA1	ENST00000692443.1 linkuse as main transcript	c.662C>T	p.Thr221Met	missense_variant	4/5	NM_033554.4	ENSP00000509163	P1
HLA-DPA1	ENST00000419277.5 linkuse as main transcript	c.662C>T	p.Thr221Met	missense_variant	5/6		ENSP00000393566	P1
HLA-DPA1	ENST00000437811.1 linkuse as main transcript	c.266C>T	p.Thr89Met	missense_variant	2/2		ENSP00000405500
HLA-DPA1	ENST00000479107.1 linkuse as main transcript	n.1261C>T		non_coding_transcript_exon_variant	2/2

Frequencies

GnomAD3 genomes

AF:

0.00618

AC:

941

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00183

Gnomad AMI

AF:

0.00877

Gnomad AMR

AF:

0.00144

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.0175

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00939

Gnomad OTH

AF:

0.00336

GnomAD3 exomes

AF:

0.00623

AC:

1536

AN:

246488

Hom.:

AF XY:

0.00595

AC XY:

800

AN XY:

134354

show subpopulations

Gnomad AFR exome

AF:

0.00113

Gnomad AMR exome

AF:

0.00133

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000547

Gnomad SAS exome

AF:

0.000856

Gnomad FIN exome

AF:

0.0171

Gnomad NFE exome

AF:

0.00949

Gnomad OTH exome

AF:

0.00461

GnomAD4 exome

AF:

0.00742

AC:

10844

AN:

1460700

Hom.:

Cov.:

AF XY:

0.00711

AC XY:

5169

AN XY:

726674

show subpopulations

Gnomad4 AFR exome

AF:

0.000836

Gnomad4 AMR exome

AF:

0.00141

Gnomad4 ASJ exome

AF:

0.000115

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000777

Gnomad4 FIN exome

AF:

0.0176

Gnomad4 NFE exome

AF:

0.00846

Gnomad4 OTH exome

AF:

0.00580

GnomAD4 genome

AF:

0.00618

AC:

941

AN:

152286

Hom.:

Cov.:

AF XY:

0.00619

AC XY:

461

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.00183

Gnomad4 AMR

AF:

0.00144

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000623

Gnomad4 FIN

AF:

0.0175

Gnomad4 NFE

AF:

0.00939

Gnomad4 OTH

AF:

0.00332

Alfa

AF:

0.00717

Hom.:

Bravo

AF:

0.00469

TwinsUK

AF:

0.00809

AC:

ALSPAC

AF:

0.00960

AC:

ESP6500AA

AF:

0.00199

AC:

ESP6500EA

AF:

0.00831

AC:

ExAC

AF:

0.00658

AC:

779

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00774

EpiControl

AF:

0.00545

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	HLA-DPA1: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 31, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.60

CADD

Benign

7.3

DANN

Benign

0.90

DEOGEN2

Benign

0.0034

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.028

MetaRNN

Benign

0.0036

MetaSVM

Benign

-0.92

MutationAssessor

Benign

1.6

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.21

PROVEAN

Benign

-1.9

REVEL

Benign

0.031

Sift

Benign

0.13

Sift4G

Benign

0.18

Polyphen

0.023

Vest4

0.048

MVP

0.014

MPC

0.50

ClinPred

0.0026

GERP RS

-2.6

Varity_R

0.016

gMVP

0.27

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over