rs707949

Positions:

• chr6-32642175-T-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_002122.5(HLA-DQA1):​c.535T>C​(p.Phe179Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.017 (12 hom., cov: 16)
  • Exomes 𝑓: 0.095 (17132 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-DQA1 NM_002122.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.18

Genes affected

HLA-DQA1 (HGNC:4942): (major histocompatibility complex, class II, DQ alpha 1) HLA-DQA1 belongs to the HLA class II alpha chain paralogues. The 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 alpha chain is approximately 33-35 kDa. It is encoded by 5 exons; exon 1 encodes the leader peptide, exons 2 and 3 encode the two extracellular domains, and exon 4 encodes the transmembrane domain and 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. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016901493).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HLA-DQA1	NM_002122.5	c.535T>C	p.Phe179Leu	missense_variant	3/5	ENST00000343139.11
HLA-DQA1	XM_006715079.5	c.535T>C	p.Phe179Leu	missense_variant	3/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HLA-DQA1	ENST00000343139.11	c.535T>C	p.Phe179Leu	missense_variant	3/5		NM_002122.5	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 1478 AN: 89304 Hom.: 12 Cov.: 16 FAILED QC

Gnomad AFR AF: 0.0135

Gnomad AMI AF: 0.00680

Gnomad AMR AF: 0.0167

Gnomad ASJ AF: 0.0251

Gnomad EAS AF: 0.00830

Gnomad SAS AF: 0.0145

Gnomad FIN AF: 0.00748

Gnomad MID AF: 0.00806

Gnomad NFE AF: 0.0207

Gnomad OTH AF: 0.0106

GnomAD3 exomes AF: 0.177 AC: 36739 AN: 207616 Hom.: 6718 AF XY: 0.180 AC XY: 20250 AN XY: 112360

Gnomad AFR exome AF: 0.129

Gnomad AMR exome AF: 0.216

Gnomad ASJ exome AF: 0.255

Gnomad EAS exome AF: 0.129

Gnomad SAS exome AF: 0.202

Gnomad FIN exome AF: 0.110

Gnomad NFE exome AF: 0.178

Gnomad OTH exome AF: 0.185

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0947 AC: 105146 AN: 1109920 Hom.: 17132 Cov.: 32 AF XY: 0.0993 AC XY: 55081 AN XY: 554592

Gnomad4 AFR exome AF: 0.0690

Gnomad4 AMR exome AF: 0.176

Gnomad4 ASJ exome AF: 0.158

Gnomad4 EAS exome AF: 0.0550

Gnomad4 SAS exome AF: 0.154

Gnomad4 FIN exome AF: 0.0602

Gnomad4 NFE exome AF: 0.0887

Gnomad4 OTH exome AF: 0.0945

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0166 AC: 1480 AN: 89396 Hom.: 12 Cov.: 16 AF XY: 0.0151 AC XY: 660 AN XY: 43640

Gnomad4 AFR AF: 0.0135

Gnomad4 AMR AF: 0.0167

Gnomad4 ASJ AF: 0.0251

Gnomad4 EAS AF: 0.00832

Gnomad4 SAS AF: 0.0148

Gnomad4 FIN AF: 0.00748

Gnomad4 NFE AF: 0.0207

Gnomad4 OTH AF: 0.0105

Alfa AF: 0.199 Hom.: 773

ExAC AF: 0.209 AC: 24496

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.42
CADD	Pathogenic	28
DANN	Uncertain	1.0
Eigen	Benign	0.022
Eigen_PC	Benign	0.13
FATHMM_MKL	Benign	0.75	D
MetaRNN	Benign	0.0017	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.00040	P;P;P;P
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-5.0	D;D;D;D
REVEL	Benign	0.19
Sift	Uncertain	0.025	D;D;D;D
Sift4G	Benign	0.068	T;T;T;T
Vest4		0.28
MutPred		0.87		Gain of catalytic residue at F179 (P = 0.052);Gain of catalytic residue at F179 (P = 0.052);Gain of catalytic residue at F179 (P = 0.052);Gain of catalytic residue at F179 (P = 0.052);
MPC		1.1
ClinPred		0.040	T
GERP RS		4.1
gMVP		0.87

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: rs707949; hg19: chr6-32609952; COSMIC: COSV58237320; COSMIC: COSV58237320;