Genetic Variant HLA-G:c.620-40G>C (chr6-29829378-G-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001384290.1(HLA-G):c.620-40G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0395 in 1,599,266 control chromosomes in the GnomAD database, including 1,732 homozygotes. 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 0.058 ( 374 hom., cov: 31)

Exomes 𝑓: 0.038 ( 1358 hom. )

Consequence

HLA-G
NM_001384290.1 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.840

Publications

3 publications found

Variant links:

Genes affected

HLA-G (HGNC:4964): (major histocompatibility complex, class I, G) HLA-G belongs to the HLA class I heavy chain paralogues. This class I molecule is a heterodimer consisting of a heavy chain and a light chain (beta-2 microglobulin). The heavy chain is anchored in the membrane. HLA-G is expressed on fetal derived placental cells. The heavy chain is approximately 45 kDa and its gene contains 8 exons. Exon one encodes the leader peptide, exons 2 and 3 encode the alpha1 and alpha2 domain, which both bind the peptide, exon 4 encodes the alpha3 domain, exon 5 encodes the transmembrane region, and exon 6 encodes the cytoplasmic tail. [provided by RefSeq, Jul 2008]

HLA-G links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.99).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.101 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001384290.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HLA-G	NM_001384290.1	MANE Select	c.620-40G>C	intron	N/A	NP_001371219.1	Q6DU14
HLA-G	NM_001363567.2		c.635-40G>C	intron	N/A	NP_001350496.1	Q5RJ85
HLA-G	NM_001384280.1		c.635-40G>C	intron	N/A	NP_001371209.1	Q5RJ85

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HLA-G	ENST00000360323.11	TSL:6 MANE Select	c.620-40G>C	intron	N/A	ENSP00000353472.6	P17693-1
HLA-G	ENST00000376828.6	TSL:6	c.635-40G>C	intron	N/A	ENSP00000366024.2	Q5RJ85
HLA-G	ENST00000936944.1		c.620-40G>C	intron	N/A	ENSP00000607003.1

Frequencies

GnomAD3 genomes

AF:

0.0577

AC:

8780

AN:

152082

Hom.:

368

Cov.:

show subpopulations

Gnomad AFR

AF:

0.104

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0852

Gnomad ASJ

AF:

0.0773

Gnomad EAS

AF:

0.00733

Gnomad SAS

AF:

0.0284

Gnomad FIN

AF:

0.0106

Gnomad MID

AF:

0.0981

Gnomad NFE

AF:

0.0361

Gnomad OTH

AF:

0.0723

GnomAD2 exomes

AF:

0.0454

AC:

10995

AN:

242330

AF XY:

0.0425

show subpopulations

Gnomad AFR exome

AF:

0.103

Gnomad AMR exome

AF:

0.0934

Gnomad ASJ exome

AF:

0.0743

Gnomad EAS exome

AF:

0.00386

Gnomad FIN exome

AF:

0.0119

Gnomad NFE exome

AF:

0.0350

Gnomad OTH exome

AF:

0.0487

GnomAD4 exome

AF:

0.0376

AC:

54423

AN:

1447066

Hom.:

1358

Cov.:

AF XY:

0.0374

AC XY:

26869

AN XY:

719010

show subpopulations

African (AFR)

AF:

0.103

AC:

3417

AN:

33136

American (AMR)

AF:

0.0941

AC:

4158

AN:

44168

Ashkenazi Jewish (ASJ)

AF:

0.0766

AC:

1924

AN:

25102

East Asian (EAS)

AF:

0.00705

AC:

279

AN:

39586

South Asian (SAS)

AF:

0.0373

AC:

3145

AN:

84326

European-Finnish (FIN)

AF:

0.0126

AC:

666

AN:

52780

Middle Eastern (MID)

AF:

0.0869

AC:

493

AN:

5674

European-Non Finnish (NFE)

AF:

0.0343

AC:

37766

AN:

1102552

Other (OTH)

AF:

0.0431

AC:

2575

AN:

59742

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

2241

4482

6723

8964

11205

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1504

3008

4512

6016

7520

<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

AF:

0.0578

AC:

8800

AN:

152200

Hom.:

374

Cov.:

AF XY:

0.0551

AC XY:

4102

AN XY:

74412

show subpopulations

African (AFR)

AF:

0.104

AC:

4298

AN:

41508

American (AMR)

AF:

0.0858

AC:

1312

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0773

AC:

268

AN:

3468

East Asian (EAS)

AF:

0.00735

AC:

AN:

5170

South Asian (SAS)

AF:

0.0288

AC:

139

AN:

4820

European-Finnish (FIN)

AF:

0.0106

AC:

112

AN:

10612

Middle Eastern (MID)

AF:

0.0952

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0361

AC:

2453

AN:

68006

Other (OTH)

AF:

0.0716

AC:

151

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

406

812

1219

1625

2031

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

188

282

376

470

<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:

0.0467

Hom.:

Bravo

AF:

0.0670

Asia WGS

AF:

0.0270

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.99

CADD

Benign

4.3

(source)

DANN

Benign

0.53

PhyloP100

-0.84

Mutation Taster

=100/0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over