rs707949

Variant names:

• chr6-32642175-T-C
• rs707949
• NM_002122.5:c.535T>C

Variant summary

Our verdict is Likely benign. The variant received -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
• Publications: 26 publications found

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

Our verdict: Likely_benign. The variant received -4 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-DQA1	NM_002122.5	c.535T>C	p.Phe179Leu	missense_variant	Exon 3 of 5	ENST00000343139.11	NP_002113.2
HLA-DQA1	XM_006715079.5	c.535T>C	p.Phe179Leu	missense_variant	Exon 3 of 4		XP_006715142.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLA-DQA1	ENST00000343139.11	c.535T>C	p.Phe179Leu	missense_variant	Exon 3 of 5	6	NM_002122.5	ENSP00000339398.5

Frequencies

GnomAD3 genomes AF: 0.0166 AC: 1478 AN: 89304 Hom.: 12 Cov.: 16

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

GnomAD2 exomes AF: 0.177 AC: 36739 AN: 207616 AF XY: 0.180

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 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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0690 AC: 1816 AN: 26334

American (AMR) AF: 0.176 AC: 6690 AN: 37978

Ashkenazi Jewish (ASJ) AF: 0.158 AC: 3153 AN: 19940

East Asian (EAS) AF: 0.0550 AC: 1870 AN: 33974

South Asian (SAS) AF: 0.154 AC: 10471 AN: 68096

European-Finnish (FIN) AF: 0.0602 AC: 2701 AN: 44832

Middle Eastern (MID) AF: 0.147 AC: 594 AN: 4040

European-Non Finnish (NFE) AF: 0.0887 AC: 73432 AN: 827940

Other (OTH) AF: 0.0945 AC: 4419 AN: 46786

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0135 AC: 347 AN: 25654

American (AMR) AF: 0.0167 AC: 128 AN: 7674

Ashkenazi Jewish (ASJ) AF: 0.0251 AC: 48 AN: 1910

East Asian (EAS) AF: 0.00832 AC: 24 AN: 2886

South Asian (SAS) AF: 0.0148 AC: 45 AN: 3034

European-Finnish (FIN) AF: 0.00748 AC: 50 AN: 6682

Middle Eastern (MID) AF: 0.00847 AC: 1 AN: 118

European-Non Finnish (NFE) AF: 0.0207 AC: 821 AN: 39704

Other (OTH) AF: 0.0105 AC: 12 AN: 1146

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.42
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.025	.;.;T;.
Eigen	Benign	0.022
Eigen_PC	Benign	0.13
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.78	.;.;T;T
MetaRNN	Benign	0.0017	T;T;T;T
MetaSVM	Benign	-1.0	T
PhyloP100		3.2
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
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

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