Genetic Variant NM_005514.8:c.1045+43A>G (chr6-31354590-T-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_005514.8(HLA-B):c.1045+43A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000147 in 1,363,882 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.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 12)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HLA-B
NM_005514.8 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.288

Publications

55 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:

ENSG00000298396 (HGNC:):

ENSG00000298396 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005514.8. 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-B	NM_005514.8	MANE Select	c.1045+43A>G		intron	N/A	NP_005505.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
HLA-B	ENST00000412585.7	TSL:6 MANE Select	c.1045+43A>G	intron	N/A	ENSP00000399168.2
HLA-B	ENST00000696559.1		c.1045+43A>G	intron	N/A	ENSP00000512717.1
HLA-B	ENST00000696560.1		c.1045+43A>G	intron	N/A	ENSP00000512718.1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

93866

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

GnomAD4 exome

AF:

0.00000147

AC:

AN:

1363882

Hom.:

Cov.:

AF XY:

0.00000147

AC XY:

AN XY:

679288

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31210

American (AMR)

AF:

0.00

AC:

AN:

41446

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22962

East Asian (EAS)

AF:

0.00

AC:

AN:

29524

South Asian (SAS)

AF:

0.00

AC:

AN:

84488

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45546

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5210

European-Non Finnish (NFE)

AF:

9.54e-7

AC:

AN:

1048666

Other (OTH)

AF:

0.0000182

AC:

AN:

54830

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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:

93866

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

44054

African (AFR)

AF:

0.00

AC:

AN:

22512

American (AMR)

AF:

0.00

AC:

AN:

7078

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2342

East Asian (EAS)

AF:

0.00

AC:

AN:

3260

South Asian (SAS)

AF:

0.00

AC:

AN:

1976

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

222

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

49254

Other (OTH)

AF:

0.00

AC:

AN:

1072

Alfa

AF:

0.00

Hom.:

860

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

(source)

DANN

Benign

0.60

PhyloP100

-0.29

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