Genetic Variant HLA-F:c.404-2637A>G (chr6-29735485-A-G) – 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.404-2637A>G 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 150,468 control chromosomes in the GnomAD database, including 11,851 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 ( 11851 hom., cov: 28)

Failed GnomAD Quality Control

Consequence

HLA-F
ENST00000465459.2 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.211

Publications

40 publications found

Variant links:

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:

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new If you want to explore the variant's impact on the transcript ENST00000465459.2, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

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=-0.88).

BA1

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000465459.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLA-F-AS1	NR_026972.1		n.1235+2481T>C		intron	N/A
	HLA-F-AS1	NR_026973.1		n.151-8346T>C		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HLA-F	ENST00000465459.2	TSL:6	c.404-2637A>G	intron	N/A	ENSP00000486947.1	A0A0D9SFW8
HLA-F-AS1	ENST00000458236.1	TSL:6	n.2378T>C	non_coding_transcript_exon	Exon 6 of 6
HLA-F-AS1	ENST00000399247.6	TSL:6	n.1235+2481T>C	intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.394

AC:

59189

AN:

150366

Hom.:

11835

Cov.:

show subpopulations

Gnomad AFR

AF:

0.307

Gnomad AMI

AF:

0.410

Gnomad AMR

AF:

0.415

Gnomad ASJ

AF:

0.500

Gnomad EAS

AF:

0.425

Gnomad SAS

AF:

0.290

Gnomad FIN

AF:

0.425

Gnomad MID

AF:

0.338

Gnomad NFE

AF:

0.436

Gnomad OTH

AF:

0.397

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AC:

AN:

Hom.:

Cov.:

AC XY:

AN XY:

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AC:

AN:

Other (OTH)

AC:

AN:

GnomAD4 genome

AF:

0.394

AC:

59235

AN:

150468

Hom.:

11851

Cov.:

AF XY:

0.393

AC XY:

28867

AN XY:

73422

show subpopulations

African (AFR)

AF:

0.307

AC:

12603

AN:

41030

American (AMR)

AF:

0.415

AC:

6280

AN:

15136

Ashkenazi Jewish (ASJ)

AF:

0.500

AC:

1735

AN:

3468

East Asian (EAS)

AF:

0.425

AC:

2178

AN:

5130

South Asian (SAS)

AF:

0.292

AC:

1396

AN:

4776

European-Finnish (FIN)

AF:

0.425

AC:

4226

AN:

9944

Middle Eastern (MID)

AF:

0.342

AC:

100

AN:

292

European-Non Finnish (NFE)

AF:

0.436

AC:

29518

AN:

67690

Other (OTH)

AF:

0.395

AC:

827

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

1701

3402

5103

6804

8505

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

550

1100

1650

2200

2750

<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.:

39550

Bravo

AF:

0.392

Asia WGS

AF:

0.325

AC:

1126

AN:

3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

5.4

(source)

DANN

Benign

0.61

PhyloP100

0.21

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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