19-17762834-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_015122.3(FCHO1):c.100G>C(p.Ala34Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A34E) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: FCHO1 NM_015122.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 3.36

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
• PP5: Variant 19-17762834-G-C is Pathogenic according to our data. 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.100G>C	p.Ala34Pro	missense_variant	5/29	ENST00000596536.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FCHO1	ENST00000596536.6	c.100G>C	p.Ala34Pro	missense_variant	5/29	5	NM_015122.3	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Immunodeficiency 76 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 10, 2021

- -

Severe congenital neutropenia Pathogenic:1

Pathogenic, no assertion criteria provided

research

Genomics Facility, Ludwig-Maximilians-Universität München

Dec 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.066	T
BayesDel_noAF	Benign	-0.14
Cadd	Pathogenic	30
Dann	Uncertain	1.0
DEOGEN2	Benign	0.35	T;T;T;T;T;.;T;T;T;T;.;.;.;T;T;.;T;T;.
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.94	D;D;.;D;D;D;D;.;D;D;D;D;D;D;D;D;.;D;D
M_CAP	Benign	0.057	D
MetaRNN	Uncertain	0.69	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.81	T
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Uncertain	0.64	T
Sift4G	Uncertain	0.0050	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		0.74
MutPred		0.68		Gain of disorder (P = 0.056);Gain of disorder (P = 0.056);Gain of disorder (P = 0.056);Gain of disorder (P = 0.056);Gain of disorder (P = 0.056);Gain of disorder (P = 0.056);Gain of disorder (P = 0.056);Gain of disorder (P = 0.056);Gain of disorder (P = 0.056);Gain of disorder (P = 0.056);Gain of disorder (P = 0.056);Gain of disorder (P = 0.056);Gain of disorder (P = 0.056);Gain of disorder (P = 0.056);Gain of disorder (P = 0.056);Gain of disorder (P = 0.056);Gain of disorder (P = 0.056);Gain of disorder (P = 0.056);.;
MVP		0.49
MPC		1.8
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.82
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: rs2086875746; hg19: chr19-17873643;