19-17762835-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM5

The NM_015122.3(FCHO1):c.101C>A(p.Ala34Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,460,880 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A34P) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FCHO1 NM_015122.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.46

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-17762834-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 805884.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FCHO1	NM_015122.3	c.101C>A	p.Ala34Glu	missense_variant	5/29	ENST00000596536.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FCHO1	ENST00000596536.6	c.101C>A	p.Ala34Glu	missense_variant	5/29	5	NM_015122.3	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251354 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135836

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460880 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726812

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Feb 10, 2021

This variant has not been reported in the literature in individuals with FCHO1-related conditions. 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant is present in population databases (rs201598105, ExAC 0.003%). This sequence change replaces alanine with glutamic acid at codon 34 of the FCHO1 protein (p.Ala34Glu). The alanine residue is highly conserved and there is a moderate physicochemical difference between alanine and glutamic acid. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Benign	-0.065	T
BayesDel_noAF	Benign	-0.32
Cadd	Pathogenic	26
Dann	Uncertain	0.99
DEOGEN2	Benign	0.078	T;T;T;T;T;.;T;T;T;T;.;.;.;T;T;.;T;T;.
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.93	D;D;.;D;D;D;D;.;D;D;D;D;D;D;D;D;.;D;D
M_CAP	Benign	0.073	D
MetaRNN	Uncertain	0.52	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Uncertain	0.64	T
Sift4G	Uncertain	0.0020	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	.;D;D;.;.;.;.;D;.;.;.;.;.;.;.;.;D;.;.
Vest4		0.64
MutPred		0.62		Gain of disorder (P = 0.0218);Gain of disorder (P = 0.0218);Gain of disorder (P = 0.0218);Gain of disorder (P = 0.0218);Gain of disorder (P = 0.0218);Gain of disorder (P = 0.0218);Gain of disorder (P = 0.0218);Gain of disorder (P = 0.0218);Gain of disorder (P = 0.0218);Gain of disorder (P = 0.0218);Gain of disorder (P = 0.0218);Gain of disorder (P = 0.0218);Gain of disorder (P = 0.0218);Gain of disorder (P = 0.0218);Gain of disorder (P = 0.0218);Gain of disorder (P = 0.0218);Gain of disorder (P = 0.0218);Gain of disorder (P = 0.0218);.;
MVP		0.32
MPC		1.7
ClinPred		0.97	D
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.83
gMVP		0.94

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

Publications

LitVar

Other links and lift over

dbSNP: rs201598105; hg19: chr19-17873644;