chr19-17762831-C-G

Variant names:

• chr19-17762831-C-G
• rs771754784
• NM_015122.3:c.97C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BS1_Supporting

The NM_015122.3(FCHO1):​c.97C>G​(p.Leu33Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,613,466 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L33P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: FCHO1 NM_015122.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.26
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• immunodeficiency 76

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.00000547 (8/1461282) while in subpopulation AMR AF = 0.000179 (8/44724). AF 95% confidence interval is 0.0000886. There are 0 homozygotes in GnomAdExome4. There are 2 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FCHO1	NM_015122.3	c.97C>G	p.Leu33Val	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.97C>G	p.Leu33Val	missense_variant	Exon 5 of 29	5	NM_015122.3	ENSP00000470731.1
FCHO1	ENST00000699212.1	c.97C>G	p.Leu33Val	missense_variant	Exon 5 of 30			ENSP00000514208.1
FCHO1	ENST00000594202.6	c.97C>G	p.Leu33Val	missense_variant	Exon 5 of 29	5		ENSP00000473001.1
FCHO1	ENST00000596309.6	c.97C>G	p.Leu33Val	missense_variant	Exon 5 of 29	4		ENSP00000470511.2
FCHO1	ENST00000596951.6	c.97C>G	p.Leu33Val	missense_variant	Exon 5 of 29	5		ENSP00000472417.1
FCHO1	ENST00000600209.6	c.97C>G	p.Leu33Val	missense_variant	Exon 5 of 29	5		ENSP00000469075.2
FCHO1	ENST00000600676.5	c.97C>G	p.Leu33Val	missense_variant	Exon 4 of 28	2		ENSP00000470493.1
FCHO1	ENST00000699176.1	c.97C>G	p.Leu33Val	missense_variant	Exon 5 of 29			ENSP00000514179.1
FCHO1	ENST00000699177.1	c.97C>G	p.Leu33Val	missense_variant	Exon 5 of 29			ENSP00000514180.1
FCHO1	ENST00000699207.1	c.97C>G	p.Leu33Val	missense_variant	Exon 5 of 29			ENSP00000514204.1
FCHO1	ENST00000699209.1	c.97C>G	p.Leu33Val	missense_variant	Exon 5 of 29			ENSP00000514206.1
FCHO1	ENST00000699215.1	c.97C>G	p.Leu33Val	missense_variant	Exon 4 of 28			ENSP00000514211.1
FCHO1	ENST00000699202.1	c.97C>G	p.Leu33Val	missense_variant	Exon 5 of 29			ENSP00000514200.1
FCHO1	ENST00000699214.1	c.97C>G	p.Leu33Val	missense_variant	Exon 4 of 28			ENSP00000514210.1
FCHO1	ENST00000699208.1	c.97C>G	p.Leu33Val	missense_variant	Exon 5 of 28			ENSP00000514205.1
FCHO1	ENST00000699198.1	c.97C>G	p.Leu33Val	missense_variant	Exon 5 of 29			ENSP00000514196.1
FCHO1	ENST00000699199.1	c.97C>G	p.Leu33Val	missense_variant	Exon 4 of 28			ENSP00000514197.1
FCHO1	ENST00000699213.1	c.97C>G	p.Leu33Val	missense_variant	Exon 4 of 28			ENSP00000514209.1
FCHO1	ENST00000699197.1	c.97C>G	p.Leu33Val	missense_variant	Exon 5 of 28			ENSP00000514195.1
FCHO1	ENST00000699200.1	c.97C>G	p.Leu33Val	missense_variant	Exon 5 of 28			ENSP00000514198.1
FCHO1	ENST00000699196.1	c.97C>G	p.Leu33Val	missense_variant	Exon 5 of 27			ENSP00000514194.1
FCHO1	ENST00000699201.1	n.97C>G		non_coding_transcript_exon_variant	Exon 5 of 28			ENSP00000514199.1
FCHO1	ENST00000699205.1	n.97C>G		non_coding_transcript_exon_variant	Exon 5 of 27			ENSP00000514202.1
FCHO1	ENST00000699206.1	n.97C>G		non_coding_transcript_exon_variant	Exon 5 of 29			ENSP00000514203.1
FCHO1	ENST00000699210.1	n.97C>G		non_coding_transcript_exon_variant	Exon 5 of 28			ENSP00000514207.1
FCHO1	ENST00000699203.1	c.-54C>G		5_prime_UTR_variant	Exon 3 of 22			ENSP00000514201.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152184 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000358 AC: 9 AN: 251398 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461282 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726994

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.000179 AC: 8 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5730

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111506

Other (OTH) AF: 0.00 AC: 0 AN: 60380

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152184 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74342

African (AFR) AF: 0.00 AC: 0 AN: 41454

American (AMR) AF: 0.0000655 AC: 1 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Feb 20, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.97C>G (p.L33V) alteration is located in exon 5 (coding exon 2) of the FCHO1 gene. This alteration results from a C to G substitution at nucleotide position 97, causing the leucine (L) at amino acid position 33 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Sep 21, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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: "Tolerated"; 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 present in population databases (rs771754784, gnomAD 0.02%). This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 33 of the FCHO1 protein (p.Leu33Val). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.043	T;T;T;T;T;.;T;T;T;T;.;.;.;T;T;.;T;T;.
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.93	D;D;.;D;D;D;D;.;D;D;D;D;D;D;D;D;.;D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.58	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.56	T
MutationAssessor	Uncertain	2.8	.;M;M;.;.;.;.;M;.;.;.;.;.;.;.;.;M;.;.
PhyloP100		2.3
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-2.4	.;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.33
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		0.77
MutPred		0.68		Loss of catalytic residue at L33 (P = 0.0554);Loss of catalytic residue at L33 (P = 0.0554);Loss of catalytic residue at L33 (P = 0.0554);Loss of catalytic residue at L33 (P = 0.0554);Loss of catalytic residue at L33 (P = 0.0554);Loss of catalytic residue at L33 (P = 0.0554);Loss of catalytic residue at L33 (P = 0.0554);Loss of catalytic residue at L33 (P = 0.0554);Loss of catalytic residue at L33 (P = 0.0554);Loss of catalytic residue at L33 (P = 0.0554);Loss of catalytic residue at L33 (P = 0.0554);Loss of catalytic residue at L33 (P = 0.0554);Loss of catalytic residue at L33 (P = 0.0554);Loss of catalytic residue at L33 (P = 0.0554);Loss of catalytic residue at L33 (P = 0.0554);Loss of catalytic residue at L33 (P = 0.0554);Loss of catalytic residue at L33 (P = 0.0554);Loss of catalytic residue at L33 (P = 0.0554);.;
MVP		0.39
MPC		1.6
ClinPred		0.88	D
GERP RS		2.1
PromoterAI		-0.0020	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.53
gMVP		0.90
Mutation Taster		=50/50

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

Other links and lift over

dbSNP: rs771754784; hg19: chr19-17873640;