chr19-17762835-C-T

Position:

chr19-17762835-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS1_Supporting

The NM_015122.3(FCHO1):c.101C>T(p.Ala34Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000304 in 1,613,102 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: 𝑓 0.000092 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000024 ( 0 hom. )

Consequence

FCHO1
NM_015122.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.46

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 links:

FCHO1 (HGNC:):

FCHO1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.15079111).

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000092 (14/152222) while in subpopulation AMR AF= 0.000786 (12/15272). AF 95% confidence interval is 0.000453. There are 0 homozygotes in gnomad4. There are 8 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FCHO1	NM_015122.3 linkuse as main transcript	c.101C>T	p.Ala34Val	missense_variant	5/29	ENST00000596536.6	NP_055937.1	O14526-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
FCHO1	ENST00000596536.6 linkuse as main transcript	c.101C>T	p.Ala34Val	missense_variant	5/29	5	NM_015122.3	ENSP00000470731.1	O14526-1
FCHO1	ENST00000699212.1 linkuse as main transcript	c.101C>T	p.Ala34Val	missense_variant	5/30			ENSP00000514208.1	A0A8V8TPN1
FCHO1	ENST00000594202.6 linkuse as main transcript	c.101C>T	p.Ala34Val	missense_variant	5/29	5		ENSP00000473001.1	A0A0C3SFZ9
FCHO1	ENST00000596309.6 linkuse as main transcript	c.101C>T	p.Ala34Val	missense_variant	5/29	4		ENSP00000470511.2	O14526-1M0QZF0
FCHO1	ENST00000596951.6 linkuse as main transcript	c.101C>T	p.Ala34Val	missense_variant	5/29	5		ENSP00000472417.1	O14526-1
FCHO1	ENST00000600209.6 linkuse as main transcript	c.101C>T	p.Ala34Val	missense_variant	5/29	5		ENSP00000469075.2	O14526-1M0QXD1
FCHO1	ENST00000600676.5 linkuse as main transcript	c.101C>T	p.Ala34Val	missense_variant	4/28	2		ENSP00000470493.1	O14526-1
FCHO1	ENST00000699176.1 linkuse as main transcript	c.101C>T	p.Ala34Val	missense_variant	5/29			ENSP00000514179.1	O14526-1
FCHO1	ENST00000699177.1 linkuse as main transcript	c.101C>T	p.Ala34Val	missense_variant	5/29			ENSP00000514180.1	O14526-1
FCHO1	ENST00000699207.1 linkuse as main transcript	c.101C>T	p.Ala34Val	missense_variant	5/29			ENSP00000514204.1	O14526-1
FCHO1	ENST00000699209.1 linkuse as main transcript	c.101C>T	p.Ala34Val	missense_variant	5/29			ENSP00000514206.1	O14526-1
FCHO1	ENST00000699215.1 linkuse as main transcript	c.101C>T	p.Ala34Val	missense_variant	4/28			ENSP00000514211.1	O14526-1
FCHO1	ENST00000699202.1 linkuse as main transcript	c.101C>T	p.Ala34Val	missense_variant	5/29			ENSP00000514200.1	A0A8V8TMX9
FCHO1	ENST00000699214.1 linkuse as main transcript	c.101C>T	p.Ala34Val	missense_variant	4/28			ENSP00000514210.1	A0A8V8TMX9
FCHO1	ENST00000699208.1 linkuse as main transcript	c.101C>T	p.Ala34Val	missense_variant	5/28			ENSP00000514205.1	A0A8V8TPA0
FCHO1	ENST00000699198.1 linkuse as main transcript	c.101C>T	p.Ala34Val	missense_variant	5/29			ENSP00000514196.1	M0QYA9
FCHO1	ENST00000699199.1 linkuse as main transcript	c.101C>T	p.Ala34Val	missense_variant	4/28			ENSP00000514197.1	M0QYA9
FCHO1	ENST00000699213.1 linkuse as main transcript	c.101C>T	p.Ala34Val	missense_variant	4/28			ENSP00000514209.1	M0QYA9
FCHO1	ENST00000699197.1 linkuse as main transcript	c.101C>T	p.Ala34Val	missense_variant	5/28			ENSP00000514195.1	A0A8V8TNC3
FCHO1	ENST00000699200.1 linkuse as main transcript	c.101C>T	p.Ala34Val	missense_variant	5/28			ENSP00000514198.1	A0A8V8TNC3
FCHO1	ENST00000699196.1 linkuse as main transcript	c.101C>T	p.Ala34Val	missense_variant	5/27			ENSP00000514194.1	A0A8V8TP91
FCHO1	ENST00000699203 linkuse as main transcript	c.-50C>T		5_prime_UTR_variant	3/22			ENSP00000514201.1	A0A8V8TPM7
FCHO1	ENST00000699201.1 linkuse as main transcript	n.101C>T		non_coding_transcript_exon_variant	5/28			ENSP00000514199.1	A0A8V8TP96
FCHO1	ENST00000699205.1 linkuse as main transcript	n.101C>T		non_coding_transcript_exon_variant	5/27			ENSP00000514202.1	A0A8V8TMV7
FCHO1	ENST00000699206.1 linkuse as main transcript	n.101C>T		non_coding_transcript_exon_variant	5/29			ENSP00000514203.1	A0A8V8TMV7
FCHO1	ENST00000699210.1 linkuse as main transcript	n.101C>T		non_coding_transcript_exon_variant	5/28			ENSP00000514207.1	A0A8V8TND1

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000787

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

GnomAD3 exomes

AF:

0.0000835

AC:

AN:

251354

Hom.:

AF XY:

0.0000589

AC XY:

AN XY:

135836

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000549

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:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000240

AC:

AN:

1460880

Hom.:

Cov.:

AF XY:

0.0000206

AC XY:

AN XY:

726812

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000402

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000117

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000920

AC:

AN:

152222

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

74422

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.000786

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00000635

Hom.:

Bravo

AF:

0.000117

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 27, 2023

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 34 of the FCHO1 protein (p.Ala34Val). This variant is present in population databases (rs201598105, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with FCHO1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1364560). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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

Benign

0.27

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.43

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.041

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

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.88

D;D;.;D;D;D;D;.;D;D;D;D;D;D;D;D;.;D;D

M_CAP

Benign

0.043

MetaRNN

Benign

0.15

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

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.9

.;L;L;.;.;.;.;L;.;.;.;.;.;.;.;.;L;.;.

PrimateAI

Uncertain

0.60

PROVEAN

Uncertain

-3.0

.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

REVEL

Benign

0.20

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

0.28

MVP

0.38

MPC

1.6

ClinPred

0.47

GERP RS

3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.50

gMVP

0.79

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over