Genetic Variant NM_005514.8:c.73+34C>A (chr6-31357052-G-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_005514.8(HLA-B):c.73+34C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. 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 0.00080 ( 0 hom., cov: 3)

Exomes 𝑓: 0.0029 ( 81 hom. )

Consequence

HLA-B
NM_005514.8 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.231

Publications

10 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:

ENSG00000271581 (HGNC:):

ENSG00000271581 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-B	NM_005514.8 link	c.73+34C>A		intron_variant	Intron 1 of 7	ENST00000412585.7	NP_005505.2	P01889E5FQ95

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLA-B	ENST00000412585.7 link	c.73+34C>A		intron_variant	Intron 1 of 7	6	NM_005514.8	ENSP00000399168.2		P01889

Frequencies

GnomAD3 genomes

AF:

0.000816

AC:

AN:

47782

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000922

Gnomad AMI

AF:

0.00352

Gnomad AMR

AF:

0.000226

Gnomad ASJ

AF:

0.000635

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00587

Gnomad FIN

AF:

0.000316

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000830

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0148

AC:

2222

AN:

149916

AF XY:

0.0156

show subpopulations

Gnomad AFR exome

AF:

0.0206

Gnomad AMR exome

AF:

0.00853

Gnomad ASJ exome

AF:

0.0240

Gnomad EAS exome

AF:

0.000887

Gnomad FIN exome

AF:

0.00280

Gnomad NFE exome

AF:

0.0151

Gnomad OTH exome

AF:

0.0168

GnomAD4 exome

AF:

0.00292

AC:

2223

AN:

761106

Hom.:

Cov.:

AF XY:

0.00336

AC XY:

1273

AN XY:

378514

show subpopulations

African (AFR)

AF:

0.00473

AC:

AN:

14384

American (AMR)

AF:

0.00261

AC:

AN:

22970

Ashkenazi Jewish (ASJ)

AF:

0.00543

AC:

AN:

16218

East Asian (EAS)

AF:

0.000242

AC:

AN:

16536

South Asian (SAS)

AF:

0.0152

AC:

610

AN:

40184

European-Finnish (FIN)

AF:

0.00103

AC:

AN:

24344

Middle Eastern (MID)

AF:

0.00484

AC:

AN:

1860

European-Non Finnish (NFE)

AF:

0.00211

AC:

1249

AN:

592962

Other (OTH)

AF:

0.00348

AC:

110

AN:

31648

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.431

Heterozygous variant carriers

147

220

294

367

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.000795

AC:

AN:

47796

Hom.:

Cov.:

AF XY:

0.000758

AC XY:

AN XY:

22432

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000828

AC:

AN:

10864

American (AMR)

AF:

0.000226

AC:

AN:

4434

Ashkenazi Jewish (ASJ)

AF:

0.000635

AC:

AN:

1574

East Asian (EAS)

AF:

0.00

AC:

AN:

820

South Asian (SAS)

AF:

0.00585

AC:

AN:

684

European-Finnish (FIN)

AF:

0.000316

AC:

AN:

3162

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.000830

AC:

AN:

25308

Other (OTH)

AF:

0.00

AC:

AN:

600

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.279

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.0118

Hom.:

943

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

6.5

(source)

DANN

Benign

0.64

PhyloP100

-0.23

PromoterAI

-0.14

Neutral

(source)

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over