6-33068771-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0510

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]

ACMG classification

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 GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HLA-DPA1	NM_033554.4	c.662C>T	p.Thr221Met	missense_variant	4/5	ENST00000692443.1
HLA-DPA1	NM_001242525.2	c.662C>T	p.Thr221Met	missense_variant	5/6
HLA-DPA1	NM_001242524.2	c.662C>T	p.Thr221Met	missense_variant	5/6
HLA-DPA1	NM_001405020.1	c.662C>T	p.Thr221Met	missense_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HLA-DPA1	ENST00000692443.1	c.662C>T	p.Thr221Met	missense_variant	4/5		NM_033554.4	P1
HLA-DPA1	ENST00000419277.5	c.662C>T	p.Thr221Met	missense_variant	5/6			P1
HLA-DPA1	ENST00000437811.1	c.266C>T	p.Thr89Met	missense_variant	2/2
HLA-DPA1	ENST00000479107.1	n.1261C>T		non_coding_transcript_exon_variant	2/2

Frequencies

GnomAD3 genomes AF: 0.00618 AC: 941 AN: 152168 Hom.: 2 Cov.: 32

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.: 10 AF XY: 0.00595 AC XY: 800 AN XY: 134354

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.: 60 Cov.: 33 AF XY: 0.00711 AC XY: 5169 AN XY: 726674

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.: 2 Cov.: 32 AF XY: 0.00619 AC XY: 461 AN XY: 74454

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.: 10

Bravo AF: 0.00469

TwinsUK AF: 0.00809 AC: 30

ALSPAC AF: 0.00960 AC: 37

ESP6500AA AF: 0.00199 AC: 6

ESP6500EA AF: 0.00831 AC: 45

ExAC AF: 0.00658 AC: 779

Asia WGS AF: 0.000577 AC: 2 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

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	Invitae	Jul 31, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	7.3
Dann	Benign	0.90
DEOGEN2	Benign	0.0034	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.028	N
MetaRNN	Benign	0.0036	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.031
Sift	Benign	0.13	T
Sift4G	Benign	0.18	T
Polyphen		0.023	B
Vest4		0.048
MVP		0.014
MPC		0.50
ClinPred		0.0026	T
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

Other links and lift over

dbSNP: rs56046206; hg19: chr6-33036548; COSMIC: COSV70090040; COSMIC: COSV70090040;