rs9274407

chr6-32665055-A-Cchr6-32665055-A-Gchr6-32665055-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002123.5(HLA-DQB1):c.122T>G(p.Phe41Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000768 in 130,260 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/18 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. F41Y) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0000077 (0 hom., cov: 20)
  • Exomes 𝑓: 8.2e-7 (0 hom.)
  • Failed GnomAD Quality Control
• 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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11160529).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HLA-DQB1	NM_002123.5	c.122T>G	p.Phe41Cys	missense_variant	2/5	ENST00000434651.7
HLA-DQB1	NM_001243961.2	c.122T>G	p.Phe41Cys	missense_variant	2/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HLA-DQB1	ENST00000434651.7	c.122T>G	p.Phe41Cys	missense_variant	2/5		NM_002123.5	P2

Frequencies

GnomAD3 genomes AF: 0.00000768 AC: 1 AN: 130260 Hom.: 0 Cov.: 20

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000168

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 8.18e-7 AC: 1 AN: 1222162 Hom.: 0 Cov.: 28 AF XY: 0.00000163 AC XY: 1 AN XY: 612118

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000109

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000768 AC: 1 AN: 130260 Hom.: 0 Cov.: 20 AF XY: 0.0000158 AC XY: 1 AN XY: 63264

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000168

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
Cadd	Benign	0.0010
Dann	Benign	0.85
DEOGEN2	Benign	0.35	T;T;.;.
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.3
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.021	T;T;.;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.11	T;T;T;T
MetaSVM	Benign	-0.59	T
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-2.3	N;N;N;N
REVEL	Benign	0.12
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Benign	0.076	T;T;T;T
Polyphen		0.81	P;.;B;B
Vest4		0.24
MutPred		0.26		Gain of ubiquitination at K44 (P = 0.0686);Gain of ubiquitination at K44 (P = 0.0686);Gain of ubiquitination at K44 (P = 0.0686);Gain of ubiquitination at K44 (P = 0.0686);
MVP		0.055
MPC		1.2
ClinPred		0.84	D
GERP RS		-8.3
gMVP		0.56

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;