6-32665055-A-T

Position:

• chr6-32665055-A-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_002123.5(HLA-DQB1):​c.122T>A​(p.Phe41Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.757 in 1,307,038 control chromosomes in the GnomAD database, including 424,334 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in Lovd as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.76 (39960 hom., cov: 20)
  • Exomes 𝑓: 0.76 (384374 hom.)
• Consequence: HLA-DQB1 NM_002123.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -7.44

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]

HLA-DQB1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.067431E-7).
• BP6: Variant 6-32665055-A-T is Benign according to our data. Variant chr6-32665055-A-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.785 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HLA-DQB1	NM_002123.5	c.122T>A	p.Phe41Tyr	missense_variant	2/5	ENST00000434651.7	NP_002114.3
HLA-DQB1	NM_001243961.2	c.122T>A	p.Phe41Tyr	missense_variant	2/6		NP_001230890.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HLA-DQB1	ENST00000434651.7	c.122T>A	p.Phe41Tyr	missense_variant	2/5	6	NM_002123.5	ENSP00000407332.2
HLA-DQB1	ENST00000374943.8	c.122T>A	p.Phe41Tyr	missense_variant	2/6	6		ENSP00000364080.4

Frequencies

GnomAD3 genomes AF: 0.757 AC: 97383 AN: 128718 Hom.: 39939 Cov.: 20

Gnomad AFR AF: 0.673

Gnomad AMI AF: 0.844

Gnomad AMR AF: 0.789

Gnomad ASJ AF: 0.910

Gnomad EAS AF: 0.723

Gnomad SAS AF: 0.757

Gnomad FIN AF: 0.734

Gnomad MID AF: 0.860

Gnomad NFE AF: 0.791

Gnomad OTH AF: 0.814

GnomAD3 exomes AF: 0.774 AC: 136420 AN: 176342 Hom.: 58580 AF XY: 0.785 AC XY: 76976 AN XY: 98052

Gnomad AFR exome AF: 0.606

Gnomad AMR exome AF: 0.751

Gnomad ASJ exome AF: 0.914

Gnomad EAS exome AF: 0.730

Gnomad SAS exome AF: 0.807

Gnomad FIN exome AF: 0.713

Gnomad NFE exome AF: 0.795

Gnomad OTH exome AF: 0.775

GnomAD4 exome AF: 0.757 AC: 892271 AN: 1178198 Hom.: 384374 Cov.: 28 AF XY: 0.760 AC XY: 449379 AN XY: 591258

Gnomad4 AFR exome AF: 0.621

Gnomad4 AMR exome AF: 0.763

Gnomad4 ASJ exome AF: 0.895

Gnomad4 EAS exome AF: 0.636

Gnomad4 SAS exome AF: 0.760

Gnomad4 FIN exome AF: 0.734

Gnomad4 NFE exome AF: 0.763

Gnomad4 OTH exome AF: 0.762

GnomAD4 genome AF: 0.756 AC: 97457 AN: 128840 Hom.: 39960 Cov.: 20 AF XY: 0.752 AC XY: 47115 AN XY: 62656

Gnomad4 AFR AF: 0.673

Gnomad4 AMR AF: 0.788

Gnomad4 ASJ AF: 0.910

Gnomad4 EAS AF: 0.722

Gnomad4 SAS AF: 0.756

Gnomad4 FIN AF: 0.734

Gnomad4 NFE AF: 0.791

Gnomad4 OTH AF: 0.812

Alfa AF: 0.644 Hom.: 1454

ESP6500AA AF: 0.719 AC: 3001

ESP6500EA AF: 0.813 AC: 6802

ExAC AF: 0.779 AC: 93224

Asia WGS AF: 0.792 AC: 2757 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.87	T
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.0010
DANN	Benign	0.69
DEOGEN2	Benign	0.0080	T;T;.;.
Eigen	Benign	-2.5
Eigen_PC	Benign	-2.7
FATHMM_MKL	Benign	0.0030	N
LIST_S2	Benign	0.0091	T;T;.;T
MetaRNN	Benign	7.1e-7	T;T;T;T
MetaSVM	Benign	-0.88	T
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.95	N;N;N;N
REVEL	Benign	0.065
Sift	Benign	1.0	T;T;T;T
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.0	B;.;B;B
Vest4		0.030
MPC		0.63
ClinPred		0.0087	T
GERP RS		-8.3
gMVP		0.31

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: rs9274407; hg19: chr6-32632832; COSMIC: COSV66570989; COSMIC: COSV66570989;