19-17762823-C-T

Variant names:

• chr19-17762823-C-T
• rs2086871298
• NM_015122.3:c.89C>T

Variant summary

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

The NM_015122.3(FCHO1):​c.89C>T​(p.Thr30Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,461,612 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: 0.0000048 (0 hom.)
• Consequence: FCHO1 NM_015122.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.31

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.4230685).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FCHO1	NM_015122.3	c.89C>T	p.Thr30Ile	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.89C>T	p.Thr30Ile	missense_variant	Exon 5 of 29	5	NM_015122.3	ENSP00000470731.1
FCHO1	ENST00000699212.1	c.89C>T	p.Thr30Ile	missense_variant	Exon 5 of 30			ENSP00000514208.1
FCHO1	ENST00000594202.6	c.89C>T	p.Thr30Ile	missense_variant	Exon 5 of 29	5		ENSP00000473001.1
FCHO1	ENST00000596309.6	c.89C>T	p.Thr30Ile	missense_variant	Exon 5 of 29	4		ENSP00000470511.2
FCHO1	ENST00000596951.6	c.89C>T	p.Thr30Ile	missense_variant	Exon 5 of 29	5		ENSP00000472417.1
FCHO1	ENST00000600209.6	c.89C>T	p.Thr30Ile	missense_variant	Exon 5 of 29	5		ENSP00000469075.2
FCHO1	ENST00000600676.5	c.89C>T	p.Thr30Ile	missense_variant	Exon 4 of 28	2		ENSP00000470493.1
FCHO1	ENST00000699176.1	c.89C>T	p.Thr30Ile	missense_variant	Exon 5 of 29			ENSP00000514179.1
FCHO1	ENST00000699177.1	c.89C>T	p.Thr30Ile	missense_variant	Exon 5 of 29			ENSP00000514180.1
FCHO1	ENST00000699207.1	c.89C>T	p.Thr30Ile	missense_variant	Exon 5 of 29			ENSP00000514204.1
FCHO1	ENST00000699209.1	c.89C>T	p.Thr30Ile	missense_variant	Exon 5 of 29			ENSP00000514206.1
FCHO1	ENST00000699215.1	c.89C>T	p.Thr30Ile	missense_variant	Exon 4 of 28			ENSP00000514211.1
FCHO1	ENST00000699202.1	c.89C>T	p.Thr30Ile	missense_variant	Exon 5 of 29			ENSP00000514200.1
FCHO1	ENST00000699214.1	c.89C>T	p.Thr30Ile	missense_variant	Exon 4 of 28			ENSP00000514210.1
FCHO1	ENST00000699208.1	c.89C>T	p.Thr30Ile	missense_variant	Exon 5 of 28			ENSP00000514205.1
FCHO1	ENST00000699198.1	c.89C>T	p.Thr30Ile	missense_variant	Exon 5 of 29			ENSP00000514196.1
FCHO1	ENST00000699199.1	c.89C>T	p.Thr30Ile	missense_variant	Exon 4 of 28			ENSP00000514197.1
FCHO1	ENST00000699213.1	c.89C>T	p.Thr30Ile	missense_variant	Exon 4 of 28			ENSP00000514209.1
FCHO1	ENST00000699197.1	c.89C>T	p.Thr30Ile	missense_variant	Exon 5 of 28			ENSP00000514195.1
FCHO1	ENST00000699200.1	c.89C>T	p.Thr30Ile	missense_variant	Exon 5 of 28			ENSP00000514198.1
FCHO1	ENST00000699196.1	c.89C>T	p.Thr30Ile	missense_variant	Exon 5 of 27			ENSP00000514194.1
FCHO1	ENST00000699203	c.-62C>T		5_prime_UTR_variant	Exon 3 of 22			ENSP00000514201.1
FCHO1	ENST00000699201.1	n.89C>T		non_coding_transcript_exon_variant	Exon 5 of 28			ENSP00000514199.1
FCHO1	ENST00000699205.1	n.89C>T		non_coding_transcript_exon_variant	Exon 5 of 27			ENSP00000514202.1
FCHO1	ENST00000699206.1	n.89C>T		non_coding_transcript_exon_variant	Exon 5 of 29			ENSP00000514203.1
FCHO1	ENST00000699210.1	n.89C>T		non_coding_transcript_exon_variant	Exon 5 of 28			ENSP00000514207.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461612 Hom.: 0 Cov.: 30 AF XY: 0.00000688 AC XY: 5 AN XY: 727144

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Oct 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 30 of the FCHO1 protein (p.Thr30Ile). This variant is not present in population databases (gnomAD no frequency). 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	Uncertain	0.40
BayesDel_addAF	Benign	-0.074	T
BayesDel_noAF	Benign	-0.34
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.076	T;T;T;T;T;.;T;T;T;T;.;.;.;T;T;.;T;T;.
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.90	D;D;.;D;D;D;D;.;D;D;D;D;D;D;D;D;.;D;D
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.42	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.3	.;M;M;.;.;.;.;M;.;.;.;.;.;.;.;.;M;.;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-4.0	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Benign	0.21
Sift	Uncertain	0.0030	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.0040	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		0.68
MutPred		0.49		Loss of disorder (P = 0.0612);Loss of disorder (P = 0.0612);Loss of disorder (P = 0.0612);Loss of disorder (P = 0.0612);Loss of disorder (P = 0.0612);Loss of disorder (P = 0.0612);Loss of disorder (P = 0.0612);Loss of disorder (P = 0.0612);Loss of disorder (P = 0.0612);Loss of disorder (P = 0.0612);Loss of disorder (P = 0.0612);Loss of disorder (P = 0.0612);Loss of disorder (P = 0.0612);Loss of disorder (P = 0.0612);Loss of disorder (P = 0.0612);Loss of disorder (P = 0.0612);Loss of disorder (P = 0.0612);Loss of disorder (P = 0.0612);.;
MVP		0.33
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		0.46
gMVP		0.84

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: rs2086871298; hg19: chr19-17873632;