rs11575907

Positions:

• chr6-32814335-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002120.4(HLA-DOB):​c.628G>A​(p.Val210Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0309 in 1,612,858 control chromosomes in the GnomAD database, including 987 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 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 same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.023 (49 hom., cov: 31)
  • Exomes 𝑓: 0.032 (938 hom.)
• Consequence: HLA-DOB NM_002120.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.542

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0023068488).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0589 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HLA-DOB	NM_002120.4	c.628G>A	p.Val210Ile	missense_variant	3/6	ENST00000438763.7	NP_002111.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HLA-DOB	ENST00000438763.7	c.628G>A	p.Val210Ile	missense_variant	3/6	6	NM_002120.4	ENSP00000390020.2
ENSG00000250264	ENST00000452392.2	c.2449G>A	p.Val817Ile	missense_variant	14/15	2		ENSP00000391806.2

Frequencies

GnomAD3 genomes AF: 0.0227 AC: 3452 AN: 152158 Hom.: 49 Cov.: 31

Gnomad AFR AF: 0.00553

Gnomad AMI AF: 0.156

Gnomad AMR AF: 0.0113

Gnomad ASJ AF: 0.0279

Gnomad EAS AF: 0.0158

Gnomad SAS AF: 0.0652

Gnomad FIN AF: 0.00896

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0334

Gnomad OTH AF: 0.0206

GnomAD3 exomes AF: 0.0270 AC: 6655 AN: 246528 Hom.: 148 AF XY: 0.0300 AC XY: 4028 AN XY: 134324

Gnomad AFR exome AF: 0.00558

Gnomad AMR exome AF: 0.00975

Gnomad ASJ exome AF: 0.0292

Gnomad EAS exome AF: 0.0181

Gnomad SAS exome AF: 0.0589

Gnomad FIN exome AF: 0.00990

Gnomad NFE exome AF: 0.0314

Gnomad OTH exome AF: 0.0229

GnomAD4 exome AF: 0.0318 AC: 46443 AN: 1460582 Hom.: 938 Cov.: 33 AF XY: 0.0326 AC XY: 23683 AN XY: 726602

Gnomad4 AFR exome AF: 0.00690

Gnomad4 AMR exome AF: 0.0107

Gnomad4 ASJ exome AF: 0.0294

Gnomad4 EAS exome AF: 0.00829

Gnomad4 SAS exome AF: 0.0572

Gnomad4 FIN exome AF: 0.0111

Gnomad4 NFE exome AF: 0.0334

Gnomad4 OTH exome AF: 0.0299

GnomAD4 genome AF: 0.0227 AC: 3451 AN: 152276 Hom.: 49 Cov.: 31 AF XY: 0.0215 AC XY: 1602 AN XY: 74464

Gnomad4 AFR AF: 0.00558

Gnomad4 AMR AF: 0.0112

Gnomad4 ASJ AF: 0.0279

Gnomad4 EAS AF: 0.0158

Gnomad4 SAS AF: 0.0648

Gnomad4 FIN AF: 0.00896

Gnomad4 NFE AF: 0.0334

Gnomad4 OTH AF: 0.0199

Alfa AF: 0.0316 Hom.: 153

Bravo AF: 0.0215

TwinsUK AF: 0.0299 AC: 111

ALSPAC AF: 0.0314 AC: 121

ESP6500AA AF: 0.00496 AC: 15

ESP6500EA AF: 0.0332 AC: 180

ExAC AF: 0.0280 AC: 3321

Asia WGS AF: 0.0230 AC: 79 AN: 3478

EpiCase AF: 0.0319

EpiControl AF: 0.0335

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	1.4
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0042	T;T;.
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.55	.;.;T
MetaRNN	Benign	0.0023	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.78	N;N;.
PROVEAN	Benign	-0.12	N;.;N
REVEL	Benign	0.040
Sift	Benign	0.76	T;.;D
Sift4G	Benign	0.87	T;.;.
Polyphen		0.011	B;B;.
Vest4		0.022
MPC		0.15
ClinPred		0.016	T
GERP RS		1.2
Varity_R		0.15
gMVP		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs11575907; hg19: chr6-32782112; COSMIC: COSV71270901; COSMIC: COSV71270901;