19-17762814-C-T

Position:

• chr19-17762814-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015122.3(FCHO1):​c.80C>T​(p.Pro27Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,788 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: 0.0000021 (0 hom.)
• Consequence: FCHO1 NM_015122.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.10

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25990236).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FCHO1	NM_015122.3	c.80C>T	p.Pro27Leu	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.80C>T	p.Pro27Leu	missense_variant	5/29	5	NM_015122.3	ENSP00000470731.1
FCHO1	ENST00000699212.1	c.80C>T	p.Pro27Leu	missense_variant	5/30			ENSP00000514208.1
FCHO1	ENST00000594202.6	c.80C>T	p.Pro27Leu	missense_variant	5/29	5		ENSP00000473001.1
FCHO1	ENST00000596309.6	c.80C>T	p.Pro27Leu	missense_variant	5/29	4		ENSP00000470511.2
FCHO1	ENST00000596951.6	c.80C>T	p.Pro27Leu	missense_variant	5/29	5		ENSP00000472417.1
FCHO1	ENST00000600209.6	c.80C>T	p.Pro27Leu	missense_variant	5/29	5		ENSP00000469075.2
FCHO1	ENST00000600676.5	c.80C>T	p.Pro27Leu	missense_variant	4/28	2		ENSP00000470493.1
FCHO1	ENST00000699176.1	c.80C>T	p.Pro27Leu	missense_variant	5/29			ENSP00000514179.1
FCHO1	ENST00000699177.1	c.80C>T	p.Pro27Leu	missense_variant	5/29			ENSP00000514180.1
FCHO1	ENST00000699207.1	c.80C>T	p.Pro27Leu	missense_variant	5/29			ENSP00000514204.1
FCHO1	ENST00000699209.1	c.80C>T	p.Pro27Leu	missense_variant	5/29			ENSP00000514206.1
FCHO1	ENST00000699215.1	c.80C>T	p.Pro27Leu	missense_variant	4/28			ENSP00000514211.1
FCHO1	ENST00000699202.1	c.80C>T	p.Pro27Leu	missense_variant	5/29			ENSP00000514200.1
FCHO1	ENST00000699214.1	c.80C>T	p.Pro27Leu	missense_variant	4/28			ENSP00000514210.1
FCHO1	ENST00000699208.1	c.80C>T	p.Pro27Leu	missense_variant	5/28			ENSP00000514205.1
FCHO1	ENST00000699198.1	c.80C>T	p.Pro27Leu	missense_variant	5/29			ENSP00000514196.1
FCHO1	ENST00000699199.1	c.80C>T	p.Pro27Leu	missense_variant	4/28			ENSP00000514197.1
FCHO1	ENST00000699213.1	c.80C>T	p.Pro27Leu	missense_variant	4/28			ENSP00000514209.1
FCHO1	ENST00000699197.1	c.80C>T	p.Pro27Leu	missense_variant	5/28			ENSP00000514195.1
FCHO1	ENST00000699200.1	c.80C>T	p.Pro27Leu	missense_variant	5/28			ENSP00000514198.1
FCHO1	ENST00000699196.1	c.80C>T	p.Pro27Leu	missense_variant	5/27			ENSP00000514194.1
FCHO1	ENST00000699203	c.-71C>T		5_prime_UTR_variant	3/22			ENSP00000514201.1
FCHO1	ENST00000699201.1	n.80C>T		non_coding_transcript_exon_variant	5/28			ENSP00000514199.1
FCHO1	ENST00000699205.1	n.80C>T		non_coding_transcript_exon_variant	5/27			ENSP00000514202.1
FCHO1	ENST00000699206.1	n.80C>T		non_coding_transcript_exon_variant	5/29			ENSP00000514203.1
FCHO1	ENST00000699210.1	n.80C>T		non_coding_transcript_exon_variant	5/28			ENSP00000514207.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000795 AC: 2 AN: 251440 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135886

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: 0.00000205 AC: 3 AN: 1461788 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 727210

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.00000756

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

Sep 08, 2023

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 27 of the FCHO1 protein (p.Pro27Leu). This variant is present in population databases (no rsID available, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with FCHO1-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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	0.10
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Uncertain	26
DANN	Uncertain	0.98
DEOGEN2	Benign	0.021	T;T;T;T;T;.;T;T;T;T;T;.;.;.;T;T;.;T;T;.
Eigen	Benign	0.066
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.90	D;D;.;D;D;D;D;D;.;D;D;D;D;D;D;D;D;.;D;D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.26	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	0.0	.;N;N;.;.;.;.;.;N;.;.;.;.;.;.;.;.;N;.;.
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-2.5	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Benign	0.15
Sift	Benign	1.0	.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.027	D;D;D;T;T;T;T;T;D;T;T;T;D;T;T;T;T;D;D;D
Polyphen		0.90	.;P;P;.;.;.;.;.;P;.;.;.;.;.;.;.;.;P;.;.
Vest4		0.37
MutPred		0.43		Loss of disorder (P = 0.0272);Loss of disorder (P = 0.0272);Loss of disorder (P = 0.0272);Loss of disorder (P = 0.0272);Loss of disorder (P = 0.0272);Loss of disorder (P = 0.0272);Loss of disorder (P = 0.0272);Loss of disorder (P = 0.0272);Loss of disorder (P = 0.0272);Loss of disorder (P = 0.0272);Loss of disorder (P = 0.0272);Loss of disorder (P = 0.0272);Loss of disorder (P = 0.0272);Loss of disorder (P = 0.0272);Loss of disorder (P = 0.0272);Loss of disorder (P = 0.0272);Loss of disorder (P = 0.0272);Loss of disorder (P = 0.0272);Loss of disorder (P = 0.0272);.;
MVP		0.16
MPC		1.2
ClinPred		0.79	D
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.10
gMVP		0.63

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: rs1019022681; hg19: chr19-17873623;