chr6-33069810-T-G

Position:

• chr6-33069810-T-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001242525.2(HLA-DPA1):​c.177A>C​(p.Glu59Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00554 in 1,610,928 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0047 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0056 (42 hom.)
• Consequence: HLA-DPA1 NM_001242525.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.12

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004793346).
• BP6: Variant 6-33069810-T-G is Benign according to our data. Variant chr6-33069810-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 2656480.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 42 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HLA-DPA1	NM_033554.4	c.177A>C	p.Glu59Asp	missense_variant	2/5	ENST00000692443.1	NP_291032.2
HLA-DPA1	NM_001242525.2	c.177A>C	p.Glu59Asp	missense_variant	3/6		NP_001229454.1
HLA-DPA1	NM_001242524.2	c.177A>C	p.Glu59Asp	missense_variant	3/6		NP_001229453.1
HLA-DPA1	NM_001405020.1	c.177A>C	p.Glu59Asp	missense_variant	2/4		NP_001391949.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HLA-DPA1	ENST00000692443.1	c.177A>C	p.Glu59Asp	missense_variant	2/5		NM_033554.4	ENSP00000509163	P1

Frequencies

GnomAD3 genomes AF: 0.00466 AC: 710 AN: 152204 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00280

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00465

Gnomad ASJ AF: 0.0242

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00579

Gnomad FIN AF: 0.00405

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00522

Gnomad OTH AF: 0.00527

GnomAD3 exomes AF: 0.00540 AC: 1332 AN: 246558 Hom.: 7 AF XY: 0.00554 AC XY: 744 AN XY: 134412

Gnomad AFR exome AF: 0.00272

Gnomad AMR exome AF: 0.00281

Gnomad ASJ exome AF: 0.0236

Gnomad EAS exome AF: 0.000602

Gnomad SAS exome AF: 0.00813

Gnomad FIN exome AF: 0.00518

Gnomad NFE exome AF: 0.00502

Gnomad OTH exome AF: 0.00543

GnomAD4 exome AF: 0.00563 AC: 8218 AN: 1458606 Hom.: 42 Cov.: 32 AF XY: 0.00571 AC XY: 4142 AN XY: 725776

Gnomad4 AFR exome AF: 0.00365

Gnomad4 AMR exome AF: 0.00275

Gnomad4 ASJ exome AF: 0.0226

Gnomad4 EAS exome AF: 0.000278

Gnomad4 SAS exome AF: 0.00799

Gnomad4 FIN exome AF: 0.00451

Gnomad4 NFE exome AF: 0.00541

Gnomad4 OTH exome AF: 0.00672

GnomAD4 genome AF: 0.00466 AC: 710 AN: 152322 Hom.: 0 Cov.: 32 AF XY: 0.00446 AC XY: 332 AN XY: 74498

Gnomad4 AFR AF: 0.00279

Gnomad4 AMR AF: 0.00464

Gnomad4 ASJ AF: 0.0242

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00580

Gnomad4 FIN AF: 0.00405

Gnomad4 NFE AF: 0.00522

Gnomad4 OTH AF: 0.00522

Alfa AF: 0.00510 Hom.: 1

Bravo AF: 0.00451

TwinsUK AF: 0.00674 AC: 25

ALSPAC AF: 0.00701 AC: 27

ESP6500AA AF: 0.00199 AC: 6

ESP6500EA AF: 0.00535 AC: 29

ExAC AF: 0.00509 AC: 598

EpiCase AF: 0.00551

EpiControl AF: 0.00539

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Mar 01, 2024

HLA-DPA1: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	1.1
DANN	Benign	0.96
DEOGEN2	Benign	0.0033	T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.033	N
M_CAP	Benign	0.0083	T
MetaRNN	Benign	0.0048	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.4	L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.28	T
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		0.0032	T
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

Other links and lift over

dbSNP: rs2308910; hg19: chr6-33037587; COSMIC: COSV99068300; COSMIC: COSV99068300;