19-17762814-C-T

Variant names:

• chr19-17762814-C-T
• rs1019022681
• NM_015122.3:c.80C>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]

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 rank	MANE	Protein	UniProt
FCHO1	NM_015122.3	c.80C>T	p.Pro27Leu	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	ENST00000596536.6	c.80C>T	p.Pro27Leu	missense_variant	Exon 5 of 29	5	NM_015122.3	ENSP00000470731.1
FCHO1	ENST00000699212.1	c.80C>T	p.Pro27Leu	missense_variant	Exon 5 of 30			ENSP00000514208.1
FCHO1	ENST00000594202.6	c.80C>T	p.Pro27Leu	missense_variant	Exon 5 of 29	5		ENSP00000473001.1
FCHO1	ENST00000596309.6	c.80C>T	p.Pro27Leu	missense_variant	Exon 5 of 29	4		ENSP00000470511.2
FCHO1	ENST00000596951.6	c.80C>T	p.Pro27Leu	missense_variant	Exon 5 of 29	5		ENSP00000472417.1
FCHO1	ENST00000600209.6	c.80C>T	p.Pro27Leu	missense_variant	Exon 5 of 29	5		ENSP00000469075.2
FCHO1	ENST00000600676.5	c.80C>T	p.Pro27Leu	missense_variant	Exon 4 of 28	2		ENSP00000470493.1
FCHO1	ENST00000699176.1	c.80C>T	p.Pro27Leu	missense_variant	Exon 5 of 29			ENSP00000514179.1
FCHO1	ENST00000699177.1	c.80C>T	p.Pro27Leu	missense_variant	Exon 5 of 29			ENSP00000514180.1
FCHO1	ENST00000699207.1	c.80C>T	p.Pro27Leu	missense_variant	Exon 5 of 29			ENSP00000514204.1
FCHO1	ENST00000699209.1	c.80C>T	p.Pro27Leu	missense_variant	Exon 5 of 29			ENSP00000514206.1
FCHO1	ENST00000699215.1	c.80C>T	p.Pro27Leu	missense_variant	Exon 4 of 28			ENSP00000514211.1
FCHO1	ENST00000699202.1	c.80C>T	p.Pro27Leu	missense_variant	Exon 5 of 29			ENSP00000514200.1
FCHO1	ENST00000699214.1	c.80C>T	p.Pro27Leu	missense_variant	Exon 4 of 28			ENSP00000514210.1
FCHO1	ENST00000699208.1	c.80C>T	p.Pro27Leu	missense_variant	Exon 5 of 28			ENSP00000514205.1
FCHO1	ENST00000699198.1	c.80C>T	p.Pro27Leu	missense_variant	Exon 5 of 29			ENSP00000514196.1
FCHO1	ENST00000699199.1	c.80C>T	p.Pro27Leu	missense_variant	Exon 4 of 28			ENSP00000514197.1
FCHO1	ENST00000699213.1	c.80C>T	p.Pro27Leu	missense_variant	Exon 4 of 28			ENSP00000514209.1
FCHO1	ENST00000699197.1	c.80C>T	p.Pro27Leu	missense_variant	Exon 5 of 28			ENSP00000514195.1
FCHO1	ENST00000699200.1	c.80C>T	p.Pro27Leu	missense_variant	Exon 5 of 28			ENSP00000514198.1
FCHO1	ENST00000699196.1	c.80C>T	p.Pro27Leu	missense_variant	Exon 5 of 27			ENSP00000514194.1
FCHO1	ENST00000699203	c.-71C>T		5_prime_UTR_variant	Exon 3 of 22			ENSP00000514201.1
FCHO1	ENST00000699201.1	n.80C>T		non_coding_transcript_exon_variant	Exon 5 of 28			ENSP00000514199.1
FCHO1	ENST00000699205.1	n.80C>T		non_coding_transcript_exon_variant	Exon 5 of 27			ENSP00000514202.1
FCHO1	ENST00000699206.1	n.80C>T		non_coding_transcript_exon_variant	Exon 5 of 29			ENSP00000514203.1
FCHO1	ENST00000699210.1	n.80C>T		non_coding_transcript_exon_variant	Exon 5 of 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

Sep 08, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). 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. 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. This variant has not been reported in the literature in individuals affected with FCHO1-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.002%). -

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;