Genetic Variant NM_002122.5:c.535T>C (chr6-32642175-T-C) – ACMG Classification: Likely_benign (-4 pts)

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.18

Publications

26 publications found

Variant links:

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]

HLA-DQA1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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 link	c.535T>C	p.Phe179Leu	missense_variant	Exon 3 of 5	ENST00000343139.11	NP_002113.2	P01909A0A173ADG5Q8MH44
HLA-DQA1	XM_006715079.5 link	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 link	c.535T>C	p.Phe179Leu	missense_variant	Exon 3 of 5	6	NM_002122.5	ENSP00000339398.5		P01909

Frequencies

GnomAD3 genomes

AF:

0.0166

AC:

1478

AN:

89304

Hom.:

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0993

AC XY:

55081

AN XY:

554592

show subpopulations

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.353

Heterozygous variant carriers

3632

7264

10895

14527

18159

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2064

4128

6192

8256

10320

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0166

AC:

1480

AN:

89396

Hom.:

Cov.:

AF XY:

0.0151

AC XY:

660

AN XY:

43640

show subpopulations

⚠️ 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:

AN:

1910

East Asian (EAS)

AF:

0.00832

AC:

AN:

2886

South Asian (SAS)

AF:

0.0148

AC:

AN:

3034

European-Finnish (FIN)

AF:

0.00748

AC:

AN:

6682

Middle Eastern (MID)

AF:

0.00847

AC:

AN:

118

European-Non Finnish (NFE)

AF:

0.0207

AC:

821

AN:

39704

Other (OTH)

AF:

0.0105

AC:

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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.285

Heterozygous variant carriers

147

293

440

586

733

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

BayesDel_noAF

Benign

-0.42

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.025

.;.;T;.

Eigen

Benign

0.022

Eigen_PC

Benign

0.13

FATHMM_MKL

Benign

0.75

LIST_S2

Benign

0.78

.;.;T;T

MetaRNN

Benign

0.0017

T;T;T;T

MetaSVM

Benign

-1.0

PhyloP100

3.2

PrimateAI

Uncertain

0.64

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

GERP RS

4.1

gMVP

0.87

Mutation Taster

=97/3

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over