19-17762834-G-A

Position:

• chr19-17762834-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_015122.3(FCHO1):​c.100G>A​(p.Ala34Thr) 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. 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: 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]

FCHO1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.39104515).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FCHO1	NM_015122.3	c.100G>A	p.Ala34Thr	missense_variant	5/29	ENST00000596536.6	NP_055937.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FCHO1	ENST00000596536.6	c.100G>A	p.Ala34Thr	missense_variant	5/29	5	NM_015122.3	ENSP00000470731.1
FCHO1	ENST00000699212.1	c.100G>A	p.Ala34Thr	missense_variant	5/30			ENSP00000514208.1
FCHO1	ENST00000594202.6	c.100G>A	p.Ala34Thr	missense_variant	5/29	5		ENSP00000473001.1
FCHO1	ENST00000596309.6	c.100G>A	p.Ala34Thr	missense_variant	5/29	4		ENSP00000470511.2
FCHO1	ENST00000596951.6	c.100G>A	p.Ala34Thr	missense_variant	5/29	5		ENSP00000472417.1
FCHO1	ENST00000600209.6	c.100G>A	p.Ala34Thr	missense_variant	5/29	5		ENSP00000469075.2
FCHO1	ENST00000600676.5	c.100G>A	p.Ala34Thr	missense_variant	4/28	2		ENSP00000470493.1
FCHO1	ENST00000699176.1	c.100G>A	p.Ala34Thr	missense_variant	5/29			ENSP00000514179.1
FCHO1	ENST00000699177.1	c.100G>A	p.Ala34Thr	missense_variant	5/29			ENSP00000514180.1
FCHO1	ENST00000699207.1	c.100G>A	p.Ala34Thr	missense_variant	5/29			ENSP00000514204.1
FCHO1	ENST00000699209.1	c.100G>A	p.Ala34Thr	missense_variant	5/29			ENSP00000514206.1
FCHO1	ENST00000699215.1	c.100G>A	p.Ala34Thr	missense_variant	4/28			ENSP00000514211.1
FCHO1	ENST00000699202.1	c.100G>A	p.Ala34Thr	missense_variant	5/29			ENSP00000514200.1
FCHO1	ENST00000699214.1	c.100G>A	p.Ala34Thr	missense_variant	4/28			ENSP00000514210.1
FCHO1	ENST00000699208.1	c.100G>A	p.Ala34Thr	missense_variant	5/28			ENSP00000514205.1
FCHO1	ENST00000699198.1	c.100G>A	p.Ala34Thr	missense_variant	5/29			ENSP00000514196.1
FCHO1	ENST00000699199.1	c.100G>A	p.Ala34Thr	missense_variant	4/28			ENSP00000514197.1
FCHO1	ENST00000699213.1	c.100G>A	p.Ala34Thr	missense_variant	4/28			ENSP00000514209.1
FCHO1	ENST00000699197.1	c.100G>A	p.Ala34Thr	missense_variant	5/28			ENSP00000514195.1
FCHO1	ENST00000699200.1	c.100G>A	p.Ala34Thr	missense_variant	5/28			ENSP00000514198.1
FCHO1	ENST00000699196.1	c.100G>A	p.Ala34Thr	missense_variant	5/27			ENSP00000514194.1
FCHO1	ENST00000699203	c.-51G>A		5_prime_UTR_variant	3/22			ENSP00000514201.1
FCHO1	ENST00000699201.1	n.100G>A		non_coding_transcript_exon_variant	5/28			ENSP00000514199.1
FCHO1	ENST00000699205.1	n.100G>A		non_coding_transcript_exon_variant	5/27			ENSP00000514202.1
FCHO1	ENST00000699206.1	n.100G>A		non_coding_transcript_exon_variant	5/29			ENSP00000514203.1
FCHO1	ENST00000699210.1	n.100G>A		non_coding_transcript_exon_variant	5/28			ENSP00000514207.1

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 14, 2021

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 has not been reported in the literature in individuals affected with FCHO1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with threonine at codon 34 of the FCHO1 protein (p.Ala34Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.034	T;T;T;T;T;.;T;T;T;T;.;.;.;T;T;.;T;T;.
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.91	D;D;.;D;D;D;D;.;D;D;D;D;D;D;D;D;.;D;D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.39	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	.;L;L;.;.;.;.;L;.;.;.;.;.;.;.;.;L;.;.
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-2.6	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Benign	0.18
Sift	Uncertain	0.027	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.096	T;T;T;D;D;D;D;T;D;D;D;D;D;D;D;D;T;D;T
Polyphen		1.0	.;D;D;.;.;.;.;D;.;.;.;.;.;.;.;.;D;.;.
Vest4		0.25
MutPred		0.51		Loss of stability (P = 0.0696);Loss of stability (P = 0.0696);Loss of stability (P = 0.0696);Loss of stability (P = 0.0696);Loss of stability (P = 0.0696);Loss of stability (P = 0.0696);Loss of stability (P = 0.0696);Loss of stability (P = 0.0696);Loss of stability (P = 0.0696);Loss of stability (P = 0.0696);Loss of stability (P = 0.0696);Loss of stability (P = 0.0696);Loss of stability (P = 0.0696);Loss of stability (P = 0.0696);Loss of stability (P = 0.0696);Loss of stability (P = 0.0696);Loss of stability (P = 0.0696);Loss of stability (P = 0.0696);.;
MVP		0.37
MPC		1.6
ClinPred		0.99	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.34
gMVP		0.76

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-17873643;