6-32816899-C-T

Variant names:

• chr6-32816899-C-T
• rs2071554
• NM_002120.4:c.53G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002120.4(HLA-DOB):​c.53G>A​(p.Arg18Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0532 in 1,612,446 control chromosomes in the GnomAD database, including 3,344 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.083 (758 hom., cov: 32)
  • Exomes 𝑓: 0.050 (2586 hom.)
• Consequence: HLA-DOB NM_002120.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.538
• Publications: 36 publications found

Genes affected

HLA-DOB (HGNC:4937): (major histocompatibility complex, class II, DO beta) HLA-DOB belongs to the HLA class II beta chain paralogues. This class II molecule is a heterodimer consisting of an alpha (DOA) and a beta chain (DOB), both anchored in the membrane. It is located in intracellular vesicles. DO suppresses peptide loading of MHC class II molecules by inhibiting HLA-DM. Class II molecules are expressed in antigen presenting cells (APC: B lymphocytes, dendritic cells, macrophages). 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. [provided by RefSeq, Jul 2008]

ENSG00000250264 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018908381).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.168 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-DOB	NM_002120.4	c.53G>A	p.Arg18Gln	missense_variant	Exon 1 of 6	ENST00000438763.7	NP_002111.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLA-DOB	ENST00000438763.7	c.53G>A	p.Arg18Gln	missense_variant	Exon 1 of 6	6	NM_002120.4	ENSP00000390020.2
ENSG00000250264	ENST00000452392.2	c.1986G>A	p.Pro662Pro	synonymous_variant	Exon 12 of 15	2		ENSP00000391806.2

Frequencies

GnomAD3 genomes AF: 0.0825 AC: 12539 AN: 151956 Hom.: 756 Cov.: 32

Gnomad AFR AF: 0.172

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0567

Gnomad ASJ AF: 0.0611

Gnomad EAS AF: 0.0613

Gnomad SAS AF: 0.0931

Gnomad FIN AF: 0.0626

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0403

Gnomad OTH AF: 0.0783

GnomAD2 exomes AF: 0.0619 AC: 15251 AN: 246484 AF XY: 0.0632

Gnomad AFR exome AF: 0.169

Gnomad AMR exome AF: 0.0377

Gnomad ASJ exome AF: 0.0626

Gnomad EAS exome AF: 0.0401

Gnomad FIN exome AF: 0.0633

Gnomad NFE exome AF: 0.0489

Gnomad OTH exome AF: 0.0629

GnomAD4 exome AF: 0.0502 AC: 73275 AN: 1460372 Hom.: 2586 Cov.: 32 AF XY: 0.0518 AC XY: 37598 AN XY: 726524

African (AFR) AF: 0.168 AC: 5605 AN: 33454

American (AMR) AF: 0.0414 AC: 1853 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.0622 AC: 1625 AN: 26132

East Asian (EAS) AF: 0.110 AC: 4373 AN: 39686

South Asian (SAS) AF: 0.0948 AC: 8174 AN: 86224

European-Finnish (FIN) AF: 0.0611 AC: 3200 AN: 52334

Middle Eastern (MID) AF: 0.0677 AC: 390 AN: 5764

European-Non Finnish (NFE) AF: 0.0403 AC: 44847 AN: 1111716

Other (OTH) AF: 0.0532 AC: 3208 AN: 60350

GnomAD4 genome AF: 0.0826 AC: 12565 AN: 152074 Hom.: 758 Cov.: 32 AF XY: 0.0836 AC XY: 6218 AN XY: 74342

African (AFR) AF: 0.172 AC: 7121 AN: 41442

American (AMR) AF: 0.0566 AC: 865 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0611 AC: 212 AN: 3470

East Asian (EAS) AF: 0.0614 AC: 318 AN: 5176

South Asian (SAS) AF: 0.0938 AC: 451 AN: 4808

European-Finnish (FIN) AF: 0.0626 AC: 663 AN: 10584

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.0403 AC: 2739 AN: 68004

Other (OTH) AF: 0.0803 AC: 169 AN: 2104

Alfa AF: 0.0557 Hom.: 1326

Bravo AF: 0.0855

TwinsUK AF: 0.0369 AC: 137

ALSPAC AF: 0.0363 AC: 140

ESP6500AA AF: 0.167 AC: 506

ESP6500EA AF: 0.0437 AC: 237

ExAC AF: 0.0669 AC: 7913

Asia WGS AF: 0.0760 AC: 266 AN: 3478

EpiCase AF: 0.0441

EpiControl AF: 0.0449

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	14
DANN	Benign	0.97
DEOGEN2	Benign	0.017	T;T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.073	N
MetaRNN	Benign	0.0019	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M;M
PhyloP100		0.54
PROVEAN	Benign	-0.67	N;.
REVEL	Benign	0.080
Sift	Uncertain	0.0050	D;.
Sift4G	Uncertain	0.016	D;.
Polyphen		0.90	P;P
Vest4		0.099
MPC		0.32
ClinPred		0.017	T
GERP RS		3.5
PromoterAI		-0.15	Neutral
Varity_R		0.026
gMVP		0.43
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2071554; hg19: chr6-32784676; COSMIC: COSV107494349; COSMIC: COSV107494349;