Genetic Variant NM_002119.4:c.360G>C (chr6-33007564-C-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_002119.4(HLA-DOA):c.360G>C(p.Lys120Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,276 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. K120K) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HLA-DOA
NM_002119.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.471

Publications

6 publications found

Variant links:

Genes affected

HLA-DOA (HGNC:4936): (major histocompatibility complex, class II, DO alpha) HLA-DOA belongs to the HLA class II alpha chain paralogues. HLA-DOA forms a heterodimer with HLA-DOB. The heterodimer, HLA-DO, is found in lysosomes in B cells and regulates HLA-DM-mediated peptide loading on MHC class II molecules. In comparison with classical HLA class II molecules, this gene exhibits very little sequence variation, especially at the protein level. [provided by RefSeq, Jul 2008]

HLA-DOA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.27906775).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002119.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLA-DOA	NM_002119.4	MANE Select	c.360G>C	p.Lys120Asn	missense	Exon 3 of 5	NP_002110.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
HLA-DOA	ENST00000229829.7	TSL:6 MANE Select	c.360G>C	p.Lys120Asn	missense	Exon 3 of 5	ENSP00000229829.3
HLA-DOA	ENST00000374813.1	TSL:6	c.193G>C	p.Val65Leu	missense	Exon 3 of 3	ENSP00000363946.1
HLA-DOA	ENST00000485901.1	TSL:6	n.71G>C		non_coding_transcript_exon	Exon 2 of 3

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

152164

Hom.:

Cov.:

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000815

AC:

AN:

245516

AF XY:

0.00000747

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1460276

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726418

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44628

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26092

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86176

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52294

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111800

Other (OTH)

AF:

0.00

AC:

AN:

60348

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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: AC0

AF:

0.00

AC:

AN:

152164

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74334

African (AFR)

AF:

0.00

AC:

AN:

41430

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68006

Other (OTH)

AF:

0.00

AC:

AN:

2090

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.62

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.59

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.19

Eigen

Benign

0.14

Eigen_PC

Benign

0.099

FATHMM_MKL

Benign

0.19

M_CAP

Benign

0.0086

MetaRNN

Benign

0.28

MetaSVM

Benign

-0.70

MutationAssessor

Uncertain

2.6

PhyloP100

0.47

PrimateAI

Benign

0.38

PROVEAN

Uncertain

-2.9

REVEL

Benign

0.12

Sift

Benign

0.16

Sift4G

Benign

0.17

Polyphen

1.0

Vest4

0.29

MutPred

0.58

Loss of ubiquitination at K120 (P = 0.0446)

MVP

0.32

MPC

0.85

ClinPred

0.91

GERP RS

4.5

Varity_R

0.29

gMVP

0.51

Mutation Taster

=65/35

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over