6-32664882-C-T

Variant summary

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

The NM_002123.5(HLA-DQB1):c.295G>A(p.Val99Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.038 in 1,188,672 control chromosomes in the GnomAD database, including 10,563 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/17 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V99D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.032 (651 hom., cov: 20)
  • Exomes 𝑓: 0.039 (9912 hom.)
• Consequence: HLA-DQB1 NM_002123.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -13.4

Genes affected

HLA-DQB1 (HGNC:4944): (major histocompatibility complex, class II, DQ beta 1) HLA-DQB1 belongs to the HLA class II beta chain paralogs. This class II molecule is a heterodimer consisting of an alpha (DQA) and a beta chain (DQB), 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 beta chain is approximately 26-28 kDa and it contains six exons. Exon 1 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. Within the DQ molecule both the alpha chain and the beta chain contain the polymorphisms specifying the peptide binding specificities, resulting in up to four different molecules. Typing for these polymorphisms is routinely done for bone marrow transplantation. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2011]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.035562098).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.201 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HLA-DQB1	NM_002123.5	c.295G>A	p.Val99Ile	missense_variant	2/5	ENST00000434651.7
HLA-DQB1	NM_001243961.2	c.295G>A	p.Val99Ile	missense_variant	2/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HLA-DQB1	ENST00000434651.7	c.295G>A	p.Val99Ile	missense_variant	2/5		NM_002123.5	P2

Frequencies

GnomAD3 genomes AF: 0.0320 AC: 3768 AN: 117780 Hom.: 652 Cov.: 20

Gnomad AFR AF: 0.0150

Gnomad AMI AF: 0.00644

Gnomad AMR AF: 0.0389

Gnomad ASJ AF: 0.0680

Gnomad EAS AF: 0.190

Gnomad SAS AF: 0.215

Gnomad FIN AF: 0.0256

Gnomad MID AF: 0.0580

Gnomad NFE AF: 0.0152

Gnomad OTH AF: 0.0371

GnomAD3 exomes AF: 0.0391 AC: 6440 AN: 164704 Hom.: 1496 AF XY: 0.0483 AC XY: 4406 AN XY: 91246

Gnomad AFR exome AF: 0.00298

Gnomad AMR exome AF: 0.0113

Gnomad ASJ exome AF: 0.0545

Gnomad EAS exome AF: 0.110

Gnomad SAS exome AF: 0.200

Gnomad FIN exome AF: 0.00289

Gnomad NFE exome AF: 0.00889

Gnomad OTH exome AF: 0.0262

GnomAD4 exome AF: 0.0386 AC: 41369 AN: 1070812 Hom.: 9912 Cov.: 28 AF XY: 0.0451 AC XY: 24504 AN XY: 543070

Gnomad4 AFR exome AF: 0.0111

Gnomad4 AMR exome AF: 0.0538

Gnomad4 ASJ exome AF: 0.0683

Gnomad4 EAS exome AF: 0.233

Gnomad4 SAS exome AF: 0.217

Gnomad4 FIN exome AF: 0.0210

Gnomad4 NFE exome AF: 0.0126

Gnomad4 OTH exome AF: 0.0451

GnomAD4 genome AF: 0.0320 AC: 3768 AN: 117860 Hom.: 651 Cov.: 20 AF XY: 0.0362 AC XY: 2077 AN XY: 57306

Gnomad4 AFR AF: 0.0150

Gnomad4 AMR AF: 0.0392

Gnomad4 ASJ AF: 0.0680

Gnomad4 EAS AF: 0.190

Gnomad4 SAS AF: 0.214

Gnomad4 FIN AF: 0.0256

Gnomad4 NFE AF: 0.0152

Gnomad4 OTH AF: 0.0392

Alfa AF: 0.0180 Hom.: 49

ExAC AF: 0.0656 AC: 7587

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	0.0010
Dann	Benign	0.74
DEOGEN2	Benign	0.00067	T;T;.;.
Eigen	Benign	-2.9
Eigen_PC	Benign	-3.0
FATHMM_MKL	Benign	0.0014	N
LIST_S2	Benign	0.32	T;T;.;T
MetaRNN	Benign	0.036	T;T;T;T
MetaSVM	Benign	-0.89	T
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.50	N;N;N;N
REVEL	Uncertain	0.31
Sift	Benign	1.0	T;T;T;T
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.0	B;.;B;B
Vest4		0.025
MPC		0.44
ClinPred		0.015	T
GERP RS		-7.6
gMVP		0.056

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: rs9274390; hg19: chr6-32632659; COSMIC: COSV66569886; COSMIC: COSV66569886;