19-17762759-C-A

Variant names:

• chr19-17762759-C-A
• rs1345164601
• NM_015122.3:c.28-3C>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

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: Splicing: ADA: 0.9757
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.70

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]

ACMG classification

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
FCHO1	NM_015122.3	c.28-3C>A		splice_region_variant, intron_variant	Intron 4 of 28	ENST00000596536.6	NP_055937.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FCHO1	ENST00000596536.6	c.28-3C>A		splice_region_variant, intron_variant	Intron 4 of 28	5	NM_015122.3	ENSP00000470731.1
FCHO1	ENST00000699212.1	c.28-3C>A		splice_region_variant, intron_variant	Intron 4 of 29			ENSP00000514208.1
FCHO1	ENST00000594202.6	c.28-3C>A		splice_region_variant, intron_variant	Intron 4 of 28	5		ENSP00000473001.1
FCHO1	ENST00000596309.6	c.28-3C>A		splice_region_variant, intron_variant	Intron 4 of 28	4		ENSP00000470511.2
FCHO1	ENST00000596951.6	c.28-3C>A		splice_region_variant, intron_variant	Intron 4 of 28	5		ENSP00000472417.1
FCHO1	ENST00000600209.6	c.28-3C>A		splice_region_variant, intron_variant	Intron 4 of 28	5		ENSP00000469075.2
FCHO1	ENST00000600676.5	c.28-3C>A		splice_region_variant, intron_variant	Intron 3 of 27	2		ENSP00000470493.1
FCHO1	ENST00000699176.1	c.28-3C>A		splice_region_variant, intron_variant	Intron 4 of 28			ENSP00000514179.1
FCHO1	ENST00000699177.1	c.28-3C>A		splice_region_variant, intron_variant	Intron 4 of 28			ENSP00000514180.1
FCHO1	ENST00000699207.1	c.28-3C>A		splice_region_variant, intron_variant	Intron 4 of 28			ENSP00000514204.1
FCHO1	ENST00000699209.1	c.28-3C>A		splice_region_variant, intron_variant	Intron 4 of 28			ENSP00000514206.1
FCHO1	ENST00000699215.1	c.28-3C>A		splice_region_variant, intron_variant	Intron 3 of 27			ENSP00000514211.1
FCHO1	ENST00000699202.1	c.28-3C>A		splice_region_variant, intron_variant	Intron 4 of 28			ENSP00000514200.1
FCHO1	ENST00000699214.1	c.28-3C>A		splice_region_variant, intron_variant	Intron 3 of 27			ENSP00000514210.1
FCHO1	ENST00000699208.1	c.28-3C>A		splice_region_variant, intron_variant	Intron 4 of 27			ENSP00000514205.1
FCHO1	ENST00000699198.1	c.28-3C>A		splice_region_variant, intron_variant	Intron 4 of 28			ENSP00000514196.1
FCHO1	ENST00000699199.1	c.28-3C>A		splice_region_variant, intron_variant	Intron 3 of 27			ENSP00000514197.1
FCHO1	ENST00000699213.1	c.28-3C>A		splice_region_variant, intron_variant	Intron 3 of 27			ENSP00000514209.1
FCHO1	ENST00000699197.1	c.28-3C>A		splice_region_variant, intron_variant	Intron 4 of 27			ENSP00000514195.1
FCHO1	ENST00000699200.1	c.28-3C>A		splice_region_variant, intron_variant	Intron 4 of 27			ENSP00000514198.1
FCHO1	ENST00000699196.1	c.28-3C>A		splice_region_variant, intron_variant	Intron 4 of 26			ENSP00000514194.1
FCHO1	ENST00000699203.1	c.-123-3C>A		splice_region_variant, intron_variant	Intron 2 of 21			ENSP00000514201.1
FCHO1	ENST00000699201.1	n.28-3C>A		splice_region_variant, intron_variant	Intron 4 of 27			ENSP00000514199.1
FCHO1	ENST00000699205.1	n.28-3C>A		splice_region_variant, intron_variant	Intron 4 of 26			ENSP00000514202.1
FCHO1	ENST00000699206.1	n.28-3C>A		splice_region_variant, intron_variant	Intron 4 of 28			ENSP00000514203.1
FCHO1	ENST00000699210.1	n.28-3C>A		splice_region_variant, intron_variant	Intron 4 of 27			ENSP00000514207.1

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

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

Other links and lift over

dbSNP: rs1345164601; hg19: chr19-17873568;