19-17762832-T-C

Position:

• chr19-17762832-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_015122.3(FCHO1):​c.98T>C​(p.Leu33Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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: 7.25

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FCHO1	NM_015122.3	c.98T>C	p.Leu33Pro	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.98T>C	p.Leu33Pro	missense_variant	5/29	5	NM_015122.3	ENSP00000470731.1
FCHO1	ENST00000699212.1	c.98T>C	p.Leu33Pro	missense_variant	5/30			ENSP00000514208.1
FCHO1	ENST00000594202.6	c.98T>C	p.Leu33Pro	missense_variant	5/29	5		ENSP00000473001.1
FCHO1	ENST00000596309.6	c.98T>C	p.Leu33Pro	missense_variant	5/29	4		ENSP00000470511.2
FCHO1	ENST00000596951.6	c.98T>C	p.Leu33Pro	missense_variant	5/29	5		ENSP00000472417.1
FCHO1	ENST00000600209.6	c.98T>C	p.Leu33Pro	missense_variant	5/29	5		ENSP00000469075.2
FCHO1	ENST00000600676.5	c.98T>C	p.Leu33Pro	missense_variant	4/28	2		ENSP00000470493.1
FCHO1	ENST00000699176.1	c.98T>C	p.Leu33Pro	missense_variant	5/29			ENSP00000514179.1
FCHO1	ENST00000699177.1	c.98T>C	p.Leu33Pro	missense_variant	5/29			ENSP00000514180.1
FCHO1	ENST00000699207.1	c.98T>C	p.Leu33Pro	missense_variant	5/29			ENSP00000514204.1
FCHO1	ENST00000699209.1	c.98T>C	p.Leu33Pro	missense_variant	5/29			ENSP00000514206.1
FCHO1	ENST00000699215.1	c.98T>C	p.Leu33Pro	missense_variant	4/28			ENSP00000514211.1
FCHO1	ENST00000699202.1	c.98T>C	p.Leu33Pro	missense_variant	5/29			ENSP00000514200.1
FCHO1	ENST00000699214.1	c.98T>C	p.Leu33Pro	missense_variant	4/28			ENSP00000514210.1
FCHO1	ENST00000699208.1	c.98T>C	p.Leu33Pro	missense_variant	5/28			ENSP00000514205.1
FCHO1	ENST00000699198.1	c.98T>C	p.Leu33Pro	missense_variant	5/29			ENSP00000514196.1
FCHO1	ENST00000699199.1	c.98T>C	p.Leu33Pro	missense_variant	4/28			ENSP00000514197.1
FCHO1	ENST00000699213.1	c.98T>C	p.Leu33Pro	missense_variant	4/28			ENSP00000514209.1
FCHO1	ENST00000699197.1	c.98T>C	p.Leu33Pro	missense_variant	5/28			ENSP00000514195.1
FCHO1	ENST00000699200.1	c.98T>C	p.Leu33Pro	missense_variant	5/28			ENSP00000514198.1
FCHO1	ENST00000699196.1	c.98T>C	p.Leu33Pro	missense_variant	5/27			ENSP00000514194.1
FCHO1	ENST00000699203	c.-53T>C		5_prime_UTR_variant	3/22			ENSP00000514201.1
FCHO1	ENST00000699201.1	n.98T>C		non_coding_transcript_exon_variant	5/28			ENSP00000514199.1
FCHO1	ENST00000699205.1	n.98T>C		non_coding_transcript_exon_variant	5/27			ENSP00000514202.1
FCHO1	ENST00000699206.1	n.98T>C		non_coding_transcript_exon_variant	5/29			ENSP00000514203.1
FCHO1	ENST00000699210.1	n.98T>C		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 05, 2022

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 (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 1393176). This variant has not been reported in the literature in individuals affected with FCHO1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 33 of the FCHO1 protein (p.Leu33Pro). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.36	T;T;T;T;T;.;T;T;T;T;.;.;.;T;T;.;T;T;.
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.94	D;D;.;D;D;D;D;.;D;D;D;D;D;D;D;D;.;D;D
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Pathogenic	3.3	.;M;M;.;.;.;.;M;.;.;.;.;.;.;.;.;M;.;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-5.7	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.68
Sift	Pathogenic	0.0	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Pathogenic	0.0	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		0.97
MutPred		0.92		Gain of disorder (P = 0.0081);Gain of disorder (P = 0.0081);Gain of disorder (P = 0.0081);Gain of disorder (P = 0.0081);Gain of disorder (P = 0.0081);Gain of disorder (P = 0.0081);Gain of disorder (P = 0.0081);Gain of disorder (P = 0.0081);Gain of disorder (P = 0.0081);Gain of disorder (P = 0.0081);Gain of disorder (P = 0.0081);Gain of disorder (P = 0.0081);Gain of disorder (P = 0.0081);Gain of disorder (P = 0.0081);Gain of disorder (P = 0.0081);Gain of disorder (P = 0.0081);Gain of disorder (P = 0.0081);Gain of disorder (P = 0.0081);.;
MVP		0.79
MPC		2.0
ClinPred		1.0	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.99

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: chr19-17873641;