dbSNP rs2596574: HLA-B:c.-858C>T (chr6-31366397-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The ENST00000696560.1(HLA-B):c.-858C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0885 in 1,402,738 control chromosomes in the GnomAD database, including 6,566 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 0.10 ( 1067 hom., cov: 32)

Exomes 𝑓: 0.087 ( 5499 hom. )

Consequence

HLA-B
ENST00000696560.1 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.138

Publications

25 publications found

Variant links:

Genes affected

HLA-B (HGNC:4932): (major histocompatibility complex, class I, B) HLA-B 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. Class I molecules play a central role in the immune system by presenting peptides derived from the endoplasmic reticulum lumen. They are expressed in nearly all cells. The heavy chain is approximately 45 kDa and its gene contains 8 exons. Exon 1 encodes the leader peptide, exon 2 and 3 encode the alpha1 and alpha2 domains, which both bind the peptide, exon 4 encodes the alpha3 domain, exon 5 encodes the transmembrane region and exons 6 and 7 encode the cytoplasmic tail. Polymorphisms within exon 2 and exon 3 are responsible for the peptide binding specificity of each class one molecule. Typing for these polymorphisms is routinely done for bone marrow and kidney transplantation. Hundreds of HLA-B alleles have been described. [provided by RefSeq, Jul 2008]

HLA-B links:

DHFRP2 (HGNC:2863): (dihydrofolate reductase pseudogene 2)

DHFRP2 links:

ENSG00000293281 (HGNC:):

ENSG00000293281 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 (BayesDel_noAF=-0.65).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.16 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DHFRP2		n.31366397G>A		intragenic_variant

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	Protein	UniProt
HLA-B	ENST00000696560.1 link	c.-858C>T	5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 10		ENSP00000512718.1	P01889
HLA-B	ENST00000696562.1 link	c.-790C>T	5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 9		ENSP00000512720.1	P01889
DHFRP2	ENST00000414224.1 link	n.502C>T	non_coding_transcript_exon_variant	Exon 1 of 1	6

Frequencies

GnomAD3 genomes

AF:

0.102

AC:

15563

AN:

151900

Hom.:

1062

Cov.:

show subpopulations

Gnomad AFR

AF:

0.163

Gnomad AMI

AF:

0.0263

Gnomad AMR

AF:

0.136

Gnomad ASJ

AF:

0.0732

Gnomad EAS

AF:

0.0266

Gnomad SAS

AF:

0.102

Gnomad FIN

AF:

0.00778

Gnomad MID

AF:

0.135

Gnomad NFE

AF:

0.0798

Gnomad OTH

AF:

0.147

GnomAD4 exome

AF:

0.0869

AC:

108629

AN:

1250720

Hom.:

5499

Cov.:

AF XY:

0.0861

AC XY:

54435

AN XY:

632236

show subpopulations

African (AFR)

AF:

0.171

AC:

4775

AN:

27908

American (AMR)

AF:

0.0999

AC:

4347

AN:

43494

Ashkenazi Jewish (ASJ)

AF:

0.0732

AC:

1773

AN:

24212

East Asian (EAS)

AF:

0.0535

AC:

2072

AN:

38762

South Asian (SAS)

AF:

0.0944

AC:

7677

AN:

81364

European-Finnish (FIN)

AF:

0.00978

AC:

517

AN:

52852

Middle Eastern (MID)

AF:

0.156

AC:

579

AN:

3712

European-Non Finnish (NFE)

AF:

0.0886

AC:

82041

AN:

925580

Other (OTH)

AF:

0.0918

AC:

4848

AN:

52836

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.526

Heterozygous variant carriers

4637

9274

13912

18549

23186

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2976

5952

8928

11904

14880

<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:

0.103

AC:

15582

AN:

152018

Hom.:

1067

Cov.:

AF XY:

0.0990

AC XY:

7358

AN XY:

74292

show subpopulations

African (AFR)

AF:

0.163

AC:

6752

AN:

41406

American (AMR)

AF:

0.136

AC:

2074

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0732

AC:

254

AN:

3470

East Asian (EAS)

AF:

0.0268

AC:

139

AN:

5182

South Asian (SAS)

AF:

0.102

AC:

489

AN:

4812

European-Finnish (FIN)

AF:

0.00778

AC:

AN:

10542

Middle Eastern (MID)

AF:

0.128

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.0798

AC:

5426

AN:

68000

Other (OTH)

AF:

0.144

AC:

305

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

710

1420

2131

2841

3551

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

168

336

504

672

840

<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:

0.0879

Hom.:

2022

Bravo

AF:

0.118

Asia WGS

AF:

0.0710

AC:

246

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.65

CADD

Benign

(source)

DANN

Benign

0.62

PhyloP100

0.14

Splicing

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