chr19-17762767-G-T

Variant names:

• chr19-17762767-G-T
• NM_015122.3:c.33G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015122.3(FCHO1):​c.33G>T​(p.Glu11Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: FCHO1 NM_015122.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.111
• Publications: 0 publications found

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]

FCHO1 Gene-Disease associations (from GenCC):

• immunodeficiency 76

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17481738).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FCHO1	NM_015122.3	c.33G>T	p.Glu11Asp	missense_variant	Exon 5 of 29	ENST00000596536.6	NP_055937.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FCHO1	ENST00000596536.6	c.33G>T	p.Glu11Asp	missense_variant	Exon 5 of 29	5	NM_015122.3	ENSP00000470731.1
FCHO1	ENST00000699212.1	c.33G>T	p.Glu11Asp	missense_variant	Exon 5 of 30			ENSP00000514208.1
FCHO1	ENST00000594202.6	c.33G>T	p.Glu11Asp	missense_variant	Exon 5 of 29	5		ENSP00000473001.1
FCHO1	ENST00000596309.6	c.33G>T	p.Glu11Asp	missense_variant	Exon 5 of 29	4		ENSP00000470511.2
FCHO1	ENST00000596951.6	c.33G>T	p.Glu11Asp	missense_variant	Exon 5 of 29	5		ENSP00000472417.1
FCHO1	ENST00000600209.6	c.33G>T	p.Glu11Asp	missense_variant	Exon 5 of 29	5		ENSP00000469075.2
FCHO1	ENST00000600676.5	c.33G>T	p.Glu11Asp	missense_variant	Exon 4 of 28	2		ENSP00000470493.1
FCHO1	ENST00000699176.1	c.33G>T	p.Glu11Asp	missense_variant	Exon 5 of 29			ENSP00000514179.1
FCHO1	ENST00000699177.1	c.33G>T	p.Glu11Asp	missense_variant	Exon 5 of 29			ENSP00000514180.1
FCHO1	ENST00000699207.1	c.33G>T	p.Glu11Asp	missense_variant	Exon 5 of 29			ENSP00000514204.1
FCHO1	ENST00000699209.1	c.33G>T	p.Glu11Asp	missense_variant	Exon 5 of 29			ENSP00000514206.1
FCHO1	ENST00000699215.1	c.33G>T	p.Glu11Asp	missense_variant	Exon 4 of 28			ENSP00000514211.1
FCHO1	ENST00000699202.1	c.33G>T	p.Glu11Asp	missense_variant	Exon 5 of 29			ENSP00000514200.1
FCHO1	ENST00000699214.1	c.33G>T	p.Glu11Asp	missense_variant	Exon 4 of 28			ENSP00000514210.1
FCHO1	ENST00000699208.1	c.33G>T	p.Glu11Asp	missense_variant	Exon 5 of 28			ENSP00000514205.1
FCHO1	ENST00000699198.1	c.33G>T	p.Glu11Asp	missense_variant	Exon 5 of 29			ENSP00000514196.1
FCHO1	ENST00000699199.1	c.33G>T	p.Glu11Asp	missense_variant	Exon 4 of 28			ENSP00000514197.1
FCHO1	ENST00000699213.1	c.33G>T	p.Glu11Asp	missense_variant	Exon 4 of 28			ENSP00000514209.1
FCHO1	ENST00000699197.1	c.33G>T	p.Glu11Asp	missense_variant	Exon 5 of 28			ENSP00000514195.1
FCHO1	ENST00000699200.1	c.33G>T	p.Glu11Asp	missense_variant	Exon 5 of 28			ENSP00000514198.1
FCHO1	ENST00000699196.1	c.33G>T	p.Glu11Asp	missense_variant	Exon 5 of 27			ENSP00000514194.1
FCHO1	ENST00000699201.1	n.33G>T		non_coding_transcript_exon_variant	Exon 5 of 28			ENSP00000514199.1
FCHO1	ENST00000699205.1	n.33G>T		non_coding_transcript_exon_variant	Exon 5 of 27			ENSP00000514202.1
FCHO1	ENST00000699206.1	n.33G>T		non_coding_transcript_exon_variant	Exon 5 of 29			ENSP00000514203.1
FCHO1	ENST00000699210.1	n.33G>T		non_coding_transcript_exon_variant	Exon 5 of 28			ENSP00000514207.1
FCHO1	ENST00000699203.1	c.-118G>T		5_prime_UTR_variant	Exon 3 of 22			ENSP00000514201.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Dec 31, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 11 of the FCHO1 protein (p.Glu11Asp). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with FCHO1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The aspartic acid amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.030	T;T;T;T;T;.;T;T;T;T;T;.;.;.;T;T;T;.;T;T;T;.
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.84	T;T;.;T;T;T;T;T;.;D;T;T;T;T;T;T;.;T;T;.;T;T
M_CAP	Benign	0.0080	T
MetaRNN	Benign	0.17	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	.;L;L;.;.;.;.;.;L;.;.;.;.;.;.;.;.;.;.;L;.;.
PhyloP100		0.11
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.5	.;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Benign	0.045
Sift	Benign	0.13	.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.21	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;.;T;T;T;T;T
Polyphen		0.0	.;B;B;.;.;.;.;.;B;.;.;.;.;.;.;.;.;.;.;B;.;.
Vest4		0.21
MutPred		0.43		Gain of ubiquitination at K12 (P = 0.1047);Gain of ubiquitination at K12 (P = 0.1047);Gain of ubiquitination at K12 (P = 0.1047);Gain of ubiquitination at K12 (P = 0.1047);Gain of ubiquitination at K12 (P = 0.1047);Gain of ubiquitination at K12 (P = 0.1047);Gain of ubiquitination at K12 (P = 0.1047);Gain of ubiquitination at K12 (P = 0.1047);Gain of ubiquitination at K12 (P = 0.1047);Gain of ubiquitination at K12 (P = 0.1047);Gain of ubiquitination at K12 (P = 0.1047);Gain of ubiquitination at K12 (P = 0.1047);Gain of ubiquitination at K12 (P = 0.1047);Gain of ubiquitination at K12 (P = 0.1047);Gain of ubiquitination at K12 (P = 0.1047);Gain of ubiquitination at K12 (P = 0.1047);Gain of ubiquitination at K12 (P = 0.1047);Gain of ubiquitination at K12 (P = 0.1047);Gain of ubiquitination at K12 (P = 0.1047);Gain of ubiquitination at K12 (P = 0.1047);Gain of ubiquitination at K12 (P = 0.1047);.;
MVP		0.15
MPC		0.54
ClinPred		0.42	T
GERP RS		-0.27
PromoterAI		-0.035	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.10
gMVP		0.71
Mutation Taster		=79/21	polymorphism

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

Other links and lift over

hg19: chr19-17873576;