NM_015122.3:c.65G>A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_015122.3(FCHO1):c.65G>A(p.Ser22Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,826 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. S22S) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

FCHO1
NM_015122.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.65

Publications

0 publications found

Variant links:

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)

FCHO1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07577124).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FCHO1	NM_015122.3 link	c.65G>A	p.Ser22Asn	missense_variant	Exon 5 of 29	ENST00000596536.6	NP_055937.1	O14526-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FCHO1	ENST00000596536.6 link	c.65G>A	p.Ser22Asn	missense_variant	Exon 5 of 29	5	NM_015122.3	ENSP00000470731.1	O14526-1
FCHO1	ENST00000699212.1 link	c.65G>A	p.Ser22Asn	missense_variant	Exon 5 of 30			ENSP00000514208.1	A0A8V8TPN1
FCHO1	ENST00000594202.6 link	c.65G>A	p.Ser22Asn	missense_variant	Exon 5 of 29	5		ENSP00000473001.1	A0A0C3SFZ9
FCHO1	ENST00000596309.6 link	c.65G>A	p.Ser22Asn	missense_variant	Exon 5 of 29	4		ENSP00000470511.2	O14526-1M0QZF0
FCHO1	ENST00000596951.6 link	c.65G>A	p.Ser22Asn	missense_variant	Exon 5 of 29	5		ENSP00000472417.1	O14526-1
FCHO1	ENST00000600209.6 link	c.65G>A	p.Ser22Asn	missense_variant	Exon 5 of 29	5		ENSP00000469075.2	O14526-1M0QXD1
FCHO1	ENST00000600676.5 link	c.65G>A	p.Ser22Asn	missense_variant	Exon 4 of 28	2		ENSP00000470493.1	O14526-1
FCHO1	ENST00000699176.1 link	c.65G>A	p.Ser22Asn	missense_variant	Exon 5 of 29			ENSP00000514179.1	O14526-1
FCHO1	ENST00000699177.1 link	c.65G>A	p.Ser22Asn	missense_variant	Exon 5 of 29			ENSP00000514180.1	O14526-1
FCHO1	ENST00000699207.1 link	c.65G>A	p.Ser22Asn	missense_variant	Exon 5 of 29			ENSP00000514204.1	O14526-1
FCHO1	ENST00000699209.1 link	c.65G>A	p.Ser22Asn	missense_variant	Exon 5 of 29			ENSP00000514206.1	O14526-1
FCHO1	ENST00000699215.1 link	c.65G>A	p.Ser22Asn	missense_variant	Exon 4 of 28			ENSP00000514211.1	O14526-1
FCHO1	ENST00000699202.1 link	c.65G>A	p.Ser22Asn	missense_variant	Exon 5 of 29			ENSP00000514200.1	A0A8V8TMX9
FCHO1	ENST00000699214.1 link	c.65G>A	p.Ser22Asn	missense_variant	Exon 4 of 28			ENSP00000514210.1	A0A8V8TMX9
FCHO1	ENST00000699208.1 link	c.65G>A	p.Ser22Asn	missense_variant	Exon 5 of 28			ENSP00000514205.1	A0A8V8TPA0
FCHO1	ENST00000699198.1 link	c.65G>A	p.Ser22Asn	missense_variant	Exon 5 of 29			ENSP00000514196.1	M0QYA9
FCHO1	ENST00000699199.1 link	c.65G>A	p.Ser22Asn	missense_variant	Exon 4 of 28			ENSP00000514197.1	M0QYA9
FCHO1	ENST00000699213.1 link	c.65G>A	p.Ser22Asn	missense_variant	Exon 4 of 28			ENSP00000514209.1	M0QYA9
FCHO1	ENST00000699197.1 link	c.65G>A	p.Ser22Asn	missense_variant	Exon 5 of 28			ENSP00000514195.1	A0A8V8TNC3
FCHO1	ENST00000699200.1 link	c.65G>A	p.Ser22Asn	missense_variant	Exon 5 of 28			ENSP00000514198.1	A0A8V8TNC3
FCHO1	ENST00000699196.1 link	c.65G>A	p.Ser22Asn	missense_variant	Exon 5 of 27			ENSP00000514194.1	A0A8V8TP91
FCHO1	ENST00000699201.1 link	n.65G>A		non_coding_transcript_exon_variant	Exon 5 of 28			ENSP00000514199.1	A0A8V8TP96
FCHO1	ENST00000699205.1 link	n.65G>A		non_coding_transcript_exon_variant	Exon 5 of 27			ENSP00000514202.1	A0A8V8TMV7
FCHO1	ENST00000699206.1 link	n.65G>A		non_coding_transcript_exon_variant	Exon 5 of 29			ENSP00000514203.1	A0A8V8TMV7
FCHO1	ENST00000699210.1 link	n.65G>A		non_coding_transcript_exon_variant	Exon 5 of 28			ENSP00000514207.1	A0A8V8TND1
FCHO1	ENST00000699203.1 link	c.-86G>A		5_prime_UTR_variant	Exon 3 of 22			ENSP00000514201.1	A0A8V8TPM7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461826

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727226

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111950

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 27, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.65G>A (p.S22N) alteration is located in exon 5 (coding exon 2) of the FCHO1 gene. This alteration results from a G to A substitution at nucleotide position 65, causing the serine (S) at amino acid position 22 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.67

CADD

Benign

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.0047

T;T;T;T;T;.;T;T;T;T;T;.;.;.;T;T;.;T;T;T;.

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.36

FATHMM_MKL

Benign

0.64

LIST_S2

Benign

0.70

T;T;.;T;T;T;T;T;.;T;T;T;T;T;T;T;T;T;.;T;T

M_CAP

Benign

0.0090

MetaRNN

Benign

0.076

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-1.6

.;N;N;.;.;.;.;.;N;.;.;.;.;.;.;.;.;.;N;.;.

PhyloP100

4.6

PrimateAI

Benign

0.47

PROVEAN

Benign

1.4

.;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

REVEL

Benign

0.069

Sift

Benign

1.0

.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

Sift4G

Benign

1.0

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

Polyphen

0.0010

.;B;B;.;.;.;.;.;B;.;.;.;.;.;.;.;.;.;B;.;.

Vest4

0.16

MutPred

0.59

Gain of catalytic residue at S22 (P = 0.0356);Gain of catalytic residue at S22 (P = 0.0356);Gain of catalytic residue at S22 (P = 0.0356);Gain of catalytic residue at S22 (P = 0.0356);Gain of catalytic residue at S22 (P = 0.0356);Gain of catalytic residue at S22 (P = 0.0356);Gain of catalytic residue at S22 (P = 0.0356);Gain of catalytic residue at S22 (P = 0.0356);Gain of catalytic residue at S22 (P = 0.0356);Gain of catalytic residue at S22 (P = 0.0356);Gain of catalytic residue at S22 (P = 0.0356);Gain of catalytic residue at S22 (P = 0.0356);Gain of catalytic residue at S22 (P = 0.0356);Gain of catalytic residue at S22 (P = 0.0356);Gain of catalytic residue at S22 (P = 0.0356);Gain of catalytic residue at S22 (P = 0.0356);Gain of catalytic residue at S22 (P = 0.0356);Gain of catalytic residue at S22 (P = 0.0356);Gain of catalytic residue at S22 (P = 0.0356);Gain of catalytic residue at S22 (P = 0.0356);.;

MVP

0.082

MPC

0.56

ClinPred

0.48

GERP RS

3.5

PromoterAI

0.018

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.042

gMVP

0.58

Mutation Taster

=94/6

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over