19-17762759-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_015122.3(FCHO1):​c.28-3C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Consequence

FCHO1
NM_015122.3 splice_region, intron

Scores

1
1
7
Splicing: ADA: 0.9757
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.70
Variant links:
Genes affected
FCHO1 (HGNC:29002): (FCH and mu domain containing endocytic adaptor 1) Enables AP-2 adaptor complex binding activity. Involved in clathrin coat assembly and clathrin-dependent endocytosis. Located in cytosol; nucleoplasm; and plasma membrane. Is active in clathrin-coated pit. Implicated in primary immunodeficiency disease. [provided by Alliance of Genome Resources, Apr 2022]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FCHO1NM_015122.3 linkc.28-3C>A splice_region_variant, intron_variant Intron 4 of 28 ENST00000596536.6 NP_055937.1 O14526-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FCHO1ENST00000596536.6 linkc.28-3C>A splice_region_variant, intron_variant Intron 4 of 28 5 NM_015122.3 ENSP00000470731.1 O14526-1
FCHO1ENST00000699212.1 linkc.28-3C>A splice_region_variant, intron_variant Intron 4 of 29 ENSP00000514208.1 A0A8V8TPN1
FCHO1ENST00000594202.6 linkc.28-3C>A splice_region_variant, intron_variant Intron 4 of 28 5 ENSP00000473001.1 A0A0C3SFZ9
FCHO1ENST00000596309.6 linkc.28-3C>A splice_region_variant, intron_variant Intron 4 of 28 4 ENSP00000470511.2 O14526-1M0QZF0
FCHO1ENST00000596951.6 linkc.28-3C>A splice_region_variant, intron_variant Intron 4 of 28 5 ENSP00000472417.1 O14526-1
FCHO1ENST00000600209.6 linkc.28-3C>A splice_region_variant, intron_variant Intron 4 of 28 5 ENSP00000469075.2 O14526-1M0QXD1
FCHO1ENST00000600676.5 linkc.28-3C>A splice_region_variant, intron_variant Intron 3 of 27 2 ENSP00000470493.1 O14526-1
FCHO1ENST00000699176.1 linkc.28-3C>A splice_region_variant, intron_variant Intron 4 of 28 ENSP00000514179.1 O14526-1
FCHO1ENST00000699177.1 linkc.28-3C>A splice_region_variant, intron_variant Intron 4 of 28 ENSP00000514180.1 O14526-1
FCHO1ENST00000699207.1 linkc.28-3C>A splice_region_variant, intron_variant Intron 4 of 28 ENSP00000514204.1 O14526-1
FCHO1ENST00000699209.1 linkc.28-3C>A splice_region_variant, intron_variant Intron 4 of 28 ENSP00000514206.1 O14526-1
FCHO1ENST00000699215.1 linkc.28-3C>A splice_region_variant, intron_variant Intron 3 of 27 ENSP00000514211.1 O14526-1
FCHO1ENST00000699202.1 linkc.28-3C>A splice_region_variant, intron_variant Intron 4 of 28 ENSP00000514200.1 A0A8V8TMX9
FCHO1ENST00000699214.1 linkc.28-3C>A splice_region_variant, intron_variant Intron 3 of 27 ENSP00000514210.1 A0A8V8TMX9
FCHO1ENST00000699208.1 linkc.28-3C>A splice_region_variant, intron_variant Intron 4 of 27 ENSP00000514205.1 A0A8V8TPA0
FCHO1ENST00000699198.1 linkc.28-3C>A splice_region_variant, intron_variant Intron 4 of 28 ENSP00000514196.1 M0QYA9
FCHO1ENST00000699199.1 linkc.28-3C>A splice_region_variant, intron_variant Intron 3 of 27 ENSP00000514197.1 M0QYA9
FCHO1ENST00000699213.1 linkc.28-3C>A splice_region_variant, intron_variant Intron 3 of 27 ENSP00000514209.1 M0QYA9
FCHO1ENST00000699197.1 linkc.28-3C>A splice_region_variant, intron_variant Intron 4 of 27 ENSP00000514195.1 A0A8V8TNC3
FCHO1ENST00000699200.1 linkc.28-3C>A splice_region_variant, intron_variant Intron 4 of 27 ENSP00000514198.1 A0A8V8TNC3
FCHO1ENST00000699196.1 linkc.28-3C>A splice_region_variant, intron_variant Intron 4 of 26 ENSP00000514194.1 A0A8V8TP91
FCHO1ENST00000699203.1 linkc.-123-3C>A splice_region_variant, intron_variant Intron 2 of 21 ENSP00000514201.1 A0A8V8TPM7
FCHO1ENST00000699201.1 linkn.28-3C>A splice_region_variant, intron_variant Intron 4 of 27 ENSP00000514199.1 A0A8V8TP96
FCHO1ENST00000699205.1 linkn.28-3C>A splice_region_variant, intron_variant Intron 4 of 26 ENSP00000514202.1 A0A8V8TMV7
FCHO1ENST00000699206.1 linkn.28-3C>A splice_region_variant, intron_variant Intron 4 of 28 ENSP00000514203.1 A0A8V8TMV7
FCHO1ENST00000699210.1 linkn.28-3C>A splice_region_variant, intron_variant Intron 4 of 27 ENSP00000514207.1 A0A8V8TND1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
31
Alfa
AF:
0.0000282
Hom.:
0

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Aug 23, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant has not been reported in the literature in individuals affected with FCHO1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 4 of the FCHO1 gene. It does not directly change the encoded amino acid sequence of the FCHO1 protein. It affects a nucleotide within the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 1499707). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
-0.039
T
BayesDel_noAF
Benign
-0.29
CADD
Benign
17
DANN
Benign
0.76
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Benign
0.34
T
M_CAP
Benign
0.023
T
MetaRNN
Pathogenic
0.76
D
Sift4G
Benign
0.72
T
Vest4
0.75
MVP
0.84
GERP RS
2.2

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
0.98
dbscSNV1_RF
Pathogenic
0.73
SpliceAI score (max)
0.030
Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1345164601; hg19: chr19-17873568; API