Genetic Variant HLA-G:c.6+76G>T (chr6-29827120-G-T) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_001363567.2(HLA-G):c.6+76G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0465 in 477,354 control chromosomes in the GnomAD database, including 804 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 ( 372 hom., cov: 32)

Exomes 𝑓: 0.041 ( 432 hom. )

Consequence

HLA-G
NM_001363567.2 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.738

Publications

35 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:

HLA-F-AS1 (HGNC:26645): (HLA-F antisense RNA 1)

HLA-F-AS1 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=-1.01).

BA1

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	Protein	UniProt
HLA-G	NM_001363567.2 link	c.6+76G>T	intron_variant	Intron 1 of 7	NP_001350496.1
HLA-G	NM_001384280.1 link	c.6+76G>T	intron_variant	Intron 2 of 8	NP_001371209.1
HLA-G	NM_002127.6 link	c.-113+76G>T	intron_variant	Intron 1 of 7	NP_002118.1	P17693-1Q6DU14

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	Protein	UniProt
HLA-G	ENST00000376828.6 link	c.6+76G>T	intron_variant	Intron 1 of 7	6	ENSP00000366024.2	Q5RJ85
HLA-G	ENST00000428701.6 link	n.66+76G>T	intron_variant	Intron 1 of 4	6
HLA-F-AS1	ENST00000849927.1 link	n.26+1351C>A	intron_variant	Intron 1 of 3
HLA-F-AS1	ENST00000849935.1 link	n.230+600C>A	intron_variant	Intron 1 of 2

Frequencies

GnomAD3 genomes

AF:

0.0577

AC:

8780

AN:

152066

Hom.:

366

Cov.:

show subpopulations

Gnomad AFR

AF:

0.103

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0851

Gnomad ASJ

AF:

0.0772

Gnomad EAS

AF:

0.00751

Gnomad SAS

AF:

0.0286

Gnomad FIN

AF:

0.0106

Gnomad MID

AF:

0.0981

Gnomad NFE

AF:

0.0361

Gnomad OTH

AF:

0.0722

GnomAD4 exome

AF:

0.0412

AC:

13410

AN:

325170

Hom.:

432

AF XY:

0.0397

AC XY:

7303

AN XY:

183826

show subpopulations

African (AFR)

AF:

0.102

AC:

911

AN:

8930

American (AMR)

AF:

0.0928

AC:

2575

AN:

27752

Ashkenazi Jewish (ASJ)

AF:

0.0766

AC:

828

AN:

10816

East Asian (EAS)

AF:

0.00463

AC:

AN:

9932

South Asian (SAS)

AF:

0.0383

AC:

2294

AN:

59962

European-Finnish (FIN)

AF:

0.0120

AC:

333

AN:

27666

Middle Eastern (MID)

AF:

0.0940

AC:

262

AN:

2788

European-Non Finnish (NFE)

AF:

0.0337

AC:

5489

AN:

162648

Other (OTH)

AF:

0.0458

AC:

672

AN:

14676

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

680

1359

2039

2718

3398

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

216

288

360

<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:

152184

Hom.:

372

Cov.:

AF XY:

0.0551

AC XY:

4096

AN XY:

74374

show subpopulations

African (AFR)

AF:

0.103

AC:

4294

AN:

41508

American (AMR)

AF:

0.0857

AC:

1311

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0772

AC:

268

AN:

3472

East Asian (EAS)

AF:

0.00753

AC:

AN:

5180

South Asian (SAS)

AF:

0.0290

AC:

140

AN:

4826

European-Finnish (FIN)

AF:

0.0106

AC:

112

AN:

10556

Middle Eastern (MID)

AF:

0.0952

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0361

AC:

2456

AN:

68020

Other (OTH)

AF:

0.0714

AC:

151

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

428

856

1284

1712

2140

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:

0.0157

Hom.:

1450

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-1.0

CADD

Benign

1.3

(source)

DANN

Benign

0.47

PhyloP100

-0.74

PromoterAI

-0.068

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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