Genetic Variant ENST00000465459.2:c.404-3389G>A (chr6-29734733-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 ENST00000465459.2(HLA-F):c.404-3389G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.394 in 151,872 control chromosomes in the GnomAD database, including 11,998 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 0.39 ( 11998 hom., cov: 31)

Consequence

HLA-F
ENST00000465459.2 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.855

Publications

42 publications found

Variant links:

COSMIC-nc: COSV67852553

Genes affected

HLA-F (HGNC:4963): (major histocompatibility complex, class I, F) This gene belongs to the HLA class I heavy chain paralogues. It encodes a non-classical heavy chain that forms a heterodimer with a beta-2 microglobulin light chain, with the heavy chain anchored in the membrane. Unlike most other HLA heavy chains, this molecule is localized in the endoplasmic reticulum and Golgi apparatus, with a small amount present at the cell surface in some cell types. It contains a divergent peptide-binding groove, and is thought to bind a restricted subset of peptides for immune presentation. This gene exhibits few polymorphisms. Multiple transcript variants encoding different isoforms have been found for this gene. These variants lack a coding exon found in transcripts from other HLA paralogues due to an altered splice acceptor site, resulting in a shorter cytoplasmic domain. [provided by RefSeq, Jul 2008]

HLA-F 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 (BayesDel_noAF=-0.93).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.432 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	Protein
HLA-F-AS1	NR_026972.1 link	n.1235+3233C>T	intron_variant	Intron 4 of 5
HLA-F-AS1	NR_026973.1 link	n.151-7594C>T	intron_variant	Intron 1 of 1
HLA-F	XM_017010813.2 link	c.1159-3389G>A	intron_variant	Intron 7 of 7	XP_016866302.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	Protein	UniProt
HLA-F	ENST00000465459.2 link	c.404-3389G>A	intron_variant	Intron 3 of 4	6	ENSP00000486947.1	A0A0D9SFW8
HLA-F-AS1	ENST00000399247.6 link	n.1235+3233C>T	intron_variant	Intron 4 of 5	6
HLA-F-AS1	ENST00000849873.1 link	n.422-7594C>T	intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

AF:

0.394

AC:

59846

AN:

151752

Hom.:

11979

Cov.:

show subpopulations

Gnomad AFR

AF:

0.308

Gnomad AMI

AF:

0.409

Gnomad AMR

AF:

0.415

Gnomad ASJ

AF:

0.498

Gnomad EAS

AF:

0.425

Gnomad SAS

AF:

0.291

Gnomad FIN

AF:

0.431

Gnomad MID

AF:

0.338

Gnomad NFE

AF:

0.436

Gnomad OTH

AF:

0.397

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.394

AC:

59902

AN:

151872

Hom.:

11998

Cov.:

AF XY:

0.394

AC XY:

29255

AN XY:

74210

show subpopulations

African (AFR)

AF:

0.308

AC:

12762

AN:

41400

American (AMR)

AF:

0.415

AC:

6343

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.498

AC:

1728

AN:

3468

East Asian (EAS)

AF:

0.425

AC:

2192

AN:

5160

South Asian (SAS)

AF:

0.294

AC:

1414

AN:

4810

European-Finnish (FIN)

AF:

0.431

AC:

4532

AN:

10518

Middle Eastern (MID)

AF:

0.342

AC:

100

AN:

292

European-Non Finnish (NFE)

AF:

0.436

AC:

29624

AN:

67920

Other (OTH)

AF:

0.396

AC:

834

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1853

3706

5560

7413

9266

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

554

1108

1662

2216

2770

<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:

0.419

Hom.:

52398

Bravo

AF:

0.392

Asia WGS

AF:

0.327

AC:

1136

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

1.2

(source)

DANN

Benign

0.42

PhyloP100

-0.85

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over