Genetic Variant HLA-G:p.Thr55Ser (chr6-29828136-A-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_001384290.1(HLA-G):c.163A>T(p.Thr55Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0396 in 1,612,984 control chromosomes in the GnomAD database, including 1,478 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.057 ( 291 hom., cov: 33)

Exomes 𝑓: 0.038 ( 1187 hom. )

Consequence

HLA-G
NM_001384290.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0840

Publications

11 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:

HCG4P8 (HGNC:22927): (HLA complex group 4 pseudogene 8)

HCG4P8 links:

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

HLA-F-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.0024591386).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0999 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	HGVSp	Effect	Exon Rank	Protein
HLA-G	NM_001384290.1	MANE Select	c.163A>T	p.Thr55Ser	missense	Exon 2 of 7	NP_001371219.1
HLA-G	NM_001363567.2		c.178A>T	p.Thr60Ser	missense	Exon 3 of 8	NP_001350496.1
HLA-G	NM_001384280.1		c.178A>T	p.Thr60Ser	missense	Exon 4 of 9	NP_001371209.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
HLA-G	ENST00000360323.11	TSL:6 MANE Select	c.163A>T	p.Thr55Ser	missense	Exon 2 of 7	ENSP00000353472.6
HLA-G	ENST00000376828.6	TSL:6	c.178A>T	p.Thr60Ser	missense	Exon 3 of 8	ENSP00000366024.2
HLA-G	ENST00000376818.7	TSL:6	c.163A>T	p.Thr55Ser	missense	Exon 2 of 6	ENSP00000366014.3

Frequencies

GnomAD3 genomes

AF:

0.0570

AC:

8662

AN:

152040

Hom.:

286

Cov.:

show subpopulations

Gnomad AFR

AF:

0.103

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0821

Gnomad ASJ

AF:

0.0761

Gnomad EAS

AF:

0.00753

Gnomad SAS

AF:

0.0281

Gnomad FIN

AF:

0.0106

Gnomad MID

AF:

0.0949

Gnomad NFE

AF:

0.0358

Gnomad OTH

AF:

0.0705

GnomAD2 exomes

AF:

0.0457

AC:

11282

AN:

247074

AF XY:

0.0429

show subpopulations

Gnomad AFR exome

AF:

0.104

Gnomad AMR exome

AF:

0.0938

Gnomad ASJ exome

AF:

0.0760

Gnomad EAS exome

AF:

0.00373

Gnomad FIN exome

AF:

0.0117

Gnomad NFE exome

AF:

0.0354

Gnomad OTH exome

AF:

0.0496

GnomAD4 exome

AF:

0.0378

AC:

55273

AN:

1460828

Hom.:

1187

Cov.:

AF XY:

0.0375

AC XY:

27281

AN XY:

726776

show subpopulations

African (AFR)

AF:

0.103

AC:

3458

AN:

33452

American (AMR)

AF:

0.0930

AC:

4153

AN:

44654

Ashkenazi Jewish (ASJ)

AF:

0.0766

AC:

2000

AN:

26098

East Asian (EAS)

AF:

0.00713

AC:

283

AN:

39686

South Asian (SAS)

AF:

0.0375

AC:

3234

AN:

86244

European-Finnish (FIN)

AF:

0.0126

AC:

663

AN:

52780

Middle Eastern (MID)

AF:

0.0866

AC:

497

AN:

5742

European-Non Finnish (NFE)

AF:

0.0345

AC:

38371

AN:

1111806

Other (OTH)

AF:

0.0433

AC:

2614

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

3837

7674

11512

15349

19186

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1536

3072

4608

6144

7680

<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:

0.0570

AC:

8680

AN:

152156

Hom.:

291

Cov.:

AF XY:

0.0543

AC XY:

4042

AN XY:

74394

show subpopulations

African (AFR)

AF:

0.102

AC:

4255

AN:

41512

American (AMR)

AF:

0.0826

AC:

1260

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.0761

AC:

264

AN:

3470

East Asian (EAS)

AF:

0.00755

AC:

AN:

5164

South Asian (SAS)

AF:

0.0286

AC:

138

AN:

4828

European-Finnish (FIN)

AF:

0.0106

AC:

112

AN:

10610

Middle Eastern (MID)

AF:

0.0918

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0358

AC:

2437

AN:

68000

Other (OTH)

AF:

0.0698

AC:

147

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

394

788

1183

1577

1971

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:

0.0443

Hom.:

Bravo

AF:

0.0665

TwinsUK

AF:

0.0324

AC:

120

ALSPAC

AF:

0.0304

AC:

117

ESP6500AA

AF:

0.0924

AC:

279

ESP6500EA

AF:

0.0380

AC:

206

ExAC

AF:

0.0444

AC:

5368

Asia WGS

AF:

0.0270

AC:

AN:

3478

EpiCase

AF:

0.0385

EpiControl

AF:

0.0411

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.64

CADD

Benign

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.019

Eigen

Benign

-0.11

Eigen_PC

Benign

-0.41

FATHMM_MKL

Benign

0.034

LIST_S2

Benign

0.27

MetaRNN

Benign

0.0025

MetaSVM

Benign

-1.1

MutationAssessor

Pathogenic

3.6

PhyloP100

-0.084

PrimateAI

Uncertain

0.60

PROVEAN

Uncertain

-3.0

REVEL

Benign

0.098

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0080

Polyphen

1.0

Vest4

0.18

MPC

0.43

ClinPred

0.078

GERP RS

-2.0

PromoterAI

-0.011

Neutral

(source)

Varity_R

0.24

gMVP

0.27

Mutation Taster

=98/2

polymorphism (auto)

(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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over