chr19-17762785-G-T

Variant names:

• chr19-17762785-G-T
• rs1423044800
• ENST00000699203.1:c.-100G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000699203.1(FCHO1):​c.-100G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,718 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FCHO1 ENST00000699203.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.00100
• Publications: 2 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.041762114).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FCHO1	NM_015122.3	c.51G>T	p.Glu17Asp	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	ENST00000699203.1	c.-100G>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 3 of 22			ENSP00000514201.1
FCHO1	ENST00000596536.6	c.51G>T	p.Glu17Asp	missense_variant	Exon 5 of 29	5	NM_015122.3	ENSP00000470731.1
FCHO1	ENST00000699212.1	c.51G>T	p.Glu17Asp	missense_variant	Exon 5 of 30			ENSP00000514208.1
FCHO1	ENST00000594202.6	c.51G>T	p.Glu17Asp	missense_variant	Exon 5 of 29	5		ENSP00000473001.1
FCHO1	ENST00000596309.6	c.51G>T	p.Glu17Asp	missense_variant	Exon 5 of 29	4		ENSP00000470511.2
FCHO1	ENST00000596951.6	c.51G>T	p.Glu17Asp	missense_variant	Exon 5 of 29	5		ENSP00000472417.1
FCHO1	ENST00000600209.6	c.51G>T	p.Glu17Asp	missense_variant	Exon 5 of 29	5		ENSP00000469075.2
FCHO1	ENST00000600676.5	c.51G>T	p.Glu17Asp	missense_variant	Exon 4 of 28	2		ENSP00000470493.1
FCHO1	ENST00000699176.1	c.51G>T	p.Glu17Asp	missense_variant	Exon 5 of 29			ENSP00000514179.1
FCHO1	ENST00000699177.1	c.51G>T	p.Glu17Asp	missense_variant	Exon 5 of 29			ENSP00000514180.1
FCHO1	ENST00000699207.1	c.51G>T	p.Glu17Asp	missense_variant	Exon 5 of 29			ENSP00000514204.1
FCHO1	ENST00000699209.1	c.51G>T	p.Glu17Asp	missense_variant	Exon 5 of 29			ENSP00000514206.1
FCHO1	ENST00000699215.1	c.51G>T	p.Glu17Asp	missense_variant	Exon 4 of 28			ENSP00000514211.1
FCHO1	ENST00000699202.1	c.51G>T	p.Glu17Asp	missense_variant	Exon 5 of 29			ENSP00000514200.1
FCHO1	ENST00000699214.1	c.51G>T	p.Glu17Asp	missense_variant	Exon 4 of 28			ENSP00000514210.1
FCHO1	ENST00000699208.1	c.51G>T	p.Glu17Asp	missense_variant	Exon 5 of 28			ENSP00000514205.1
FCHO1	ENST00000699198.1	c.51G>T	p.Glu17Asp	missense_variant	Exon 5 of 29			ENSP00000514196.1
FCHO1	ENST00000699199.1	c.51G>T	p.Glu17Asp	missense_variant	Exon 4 of 28			ENSP00000514197.1
FCHO1	ENST00000699213.1	c.51G>T	p.Glu17Asp	missense_variant	Exon 4 of 28			ENSP00000514209.1
FCHO1	ENST00000699197.1	c.51G>T	p.Glu17Asp	missense_variant	Exon 5 of 28			ENSP00000514195.1
FCHO1	ENST00000699200.1	c.51G>T	p.Glu17Asp	missense_variant	Exon 5 of 28			ENSP00000514198.1
FCHO1	ENST00000699196.1	c.51G>T	p.Glu17Asp	missense_variant	Exon 5 of 27			ENSP00000514194.1
FCHO1	ENST00000699201.1	n.51G>T		non_coding_transcript_exon_variant	Exon 5 of 28			ENSP00000514199.1
FCHO1	ENST00000699205.1	n.51G>T		non_coding_transcript_exon_variant	Exon 5 of 27			ENSP00000514202.1
FCHO1	ENST00000699206.1	n.51G>T		non_coding_transcript_exon_variant	Exon 5 of 29			ENSP00000514203.1
FCHO1	ENST00000699210.1	n.51G>T		non_coding_transcript_exon_variant	Exon 5 of 28			ENSP00000514207.1
FCHO1	ENST00000699203.1	c.-100G>T		5_prime_UTR_variant	Exon 3 of 22			ENSP00000514201.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251462 AF XY: 0.00000736

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461718 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727196

African (AFR) AF: 0.0000299 AC: 1 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111856

Other (OTH) AF: 0.0000166 AC: 1 AN: 60390

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Mar 07, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. This sequence change replaces glutamic acid with aspartic acid at codon 17 of the FCHO1 protein (p.Glu17Asp). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with FCHO1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The aspartic acid amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	15
DANN	Benign	0.82
DEOGEN2	Benign	0.0036	T;T;T;T;T;.;T;T;T;T;T;.;.;.;T;T;.;T;T;T;.
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.79	T;T;.;T;T;T;T;T;.;T;T;T;T;T;T;T;T;T;.;T;T
M_CAP	Benign	0.0048	T
MetaRNN	Benign	0.042	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	-1.1	.;N;N;.;.;.;.;.;N;.;.;.;.;.;.;.;.;.;N;.;.
PhyloP100		0.0010
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	1.3	.;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Benign	0.048
Sift	Benign	1.0	.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	1.0	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0020	.;B;B;.;.;.;.;.;B;.;.;.;.;.;.;.;.;.;B;.;.
Vest4		0.15
MutPred		0.48		Loss of ubiquitination at K12 (P = 0.1343);Loss of ubiquitination at K12 (P = 0.1343);Loss of ubiquitination at K12 (P = 0.1343);Loss of ubiquitination at K12 (P = 0.1343);Loss of ubiquitination at K12 (P = 0.1343);Loss of ubiquitination at K12 (P = 0.1343);Loss of ubiquitination at K12 (P = 0.1343);Loss of ubiquitination at K12 (P = 0.1343);Loss of ubiquitination at K12 (P = 0.1343);Loss of ubiquitination at K12 (P = 0.1343);Loss of ubiquitination at K12 (P = 0.1343);Loss of ubiquitination at K12 (P = 0.1343);Loss of ubiquitination at K12 (P = 0.1343);Loss of ubiquitination at K12 (P = 0.1343);Loss of ubiquitination at K12 (P = 0.1343);Loss of ubiquitination at K12 (P = 0.1343);Loss of ubiquitination at K12 (P = 0.1343);Loss of ubiquitination at K12 (P = 0.1343);Loss of ubiquitination at K12 (P = 0.1343);Loss of ubiquitination at K12 (P = 0.1343);.;
MVP		0.21
MPC		0.55
ClinPred		0.070	T
GERP RS		-0.80
PromoterAI		0.016	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.062
gMVP		0.69
Mutation Taster		=80/20	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

dbSNP: rs1423044800; hg19: chr19-17873594; COSMIC: COSV53180669; COSMIC: COSV53180669;