19-17762834-G-C

Position:

• chr19-17762834-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_015122.3(FCHO1):​c.100G>C​(p.Ala34Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: FCHO1 NM_015122.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 3.36

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-17762834-G-C is Pathogenic according to our data. Variant chr19-17762834-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 805884.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FCHO1	NM_015122.3	c.100G>C	p.Ala34Pro	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.100G>C	p.Ala34Pro	missense_variant	5/29	5	NM_015122.3	ENSP00000470731.1
FCHO1	ENST00000699212.1	c.100G>C	p.Ala34Pro	missense_variant	5/30			ENSP00000514208.1
FCHO1	ENST00000594202.6	c.100G>C	p.Ala34Pro	missense_variant	5/29	5		ENSP00000473001.1
FCHO1	ENST00000596309.6	c.100G>C	p.Ala34Pro	missense_variant	5/29	4		ENSP00000470511.2
FCHO1	ENST00000596951.6	c.100G>C	p.Ala34Pro	missense_variant	5/29	5		ENSP00000472417.1
FCHO1	ENST00000600209.6	c.100G>C	p.Ala34Pro	missense_variant	5/29	5		ENSP00000469075.2
FCHO1	ENST00000600676.5	c.100G>C	p.Ala34Pro	missense_variant	4/28	2		ENSP00000470493.1
FCHO1	ENST00000699176.1	c.100G>C	p.Ala34Pro	missense_variant	5/29			ENSP00000514179.1
FCHO1	ENST00000699177.1	c.100G>C	p.Ala34Pro	missense_variant	5/29			ENSP00000514180.1
FCHO1	ENST00000699207.1	c.100G>C	p.Ala34Pro	missense_variant	5/29			ENSP00000514204.1
FCHO1	ENST00000699209.1	c.100G>C	p.Ala34Pro	missense_variant	5/29			ENSP00000514206.1
FCHO1	ENST00000699215.1	c.100G>C	p.Ala34Pro	missense_variant	4/28			ENSP00000514211.1
FCHO1	ENST00000699202.1	c.100G>C	p.Ala34Pro	missense_variant	5/29			ENSP00000514200.1
FCHO1	ENST00000699214.1	c.100G>C	p.Ala34Pro	missense_variant	4/28			ENSP00000514210.1
FCHO1	ENST00000699208.1	c.100G>C	p.Ala34Pro	missense_variant	5/28			ENSP00000514205.1
FCHO1	ENST00000699198.1	c.100G>C	p.Ala34Pro	missense_variant	5/29			ENSP00000514196.1
FCHO1	ENST00000699199.1	c.100G>C	p.Ala34Pro	missense_variant	4/28			ENSP00000514197.1
FCHO1	ENST00000699213.1	c.100G>C	p.Ala34Pro	missense_variant	4/28			ENSP00000514209.1
FCHO1	ENST00000699197.1	c.100G>C	p.Ala34Pro	missense_variant	5/28			ENSP00000514195.1
FCHO1	ENST00000699200.1	c.100G>C	p.Ala34Pro	missense_variant	5/28			ENSP00000514198.1
FCHO1	ENST00000699196.1	c.100G>C	p.Ala34Pro	missense_variant	5/27			ENSP00000514194.1
FCHO1	ENST00000699203	c.-51G>C		5_prime_UTR_variant	3/22			ENSP00000514201.1
FCHO1	ENST00000699201.1	n.100G>C		non_coding_transcript_exon_variant	5/28			ENSP00000514199.1
FCHO1	ENST00000699205.1	n.100G>C		non_coding_transcript_exon_variant	5/27			ENSP00000514202.1
FCHO1	ENST00000699206.1	n.100G>C		non_coding_transcript_exon_variant	5/29			ENSP00000514203.1
FCHO1	ENST00000699210.1	n.100G>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: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Immunodeficiency 76 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 10, 2021

- -

Severe congenital neutropenia Pathogenic:1

Pathogenic, no assertion criteria provided

research

Genomics Facility, Ludwig-Maximilians-Universität München

Dec 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.066	T
BayesDel_noAF	Benign	-0.14
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T;T;T;T;T;.;T;T;T;T;.;.;.;T;T;.;T;T;.
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.94	D;D;.;D;D;D;D;.;D;D;D;D;D;D;D;D;.;D;D
M_CAP	Benign	0.057	D
MetaRNN	Uncertain	0.69	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.81	T
MutationAssessor	Pathogenic	3.0	.;M;M;.;.;.;.;M;.;.;.;.;.;.;.;.;M;.;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.6	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.36
Sift	Uncertain	0.0040	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.0050	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		0.74
MutPred		0.68		Gain of disorder (P = 0.056);Gain of disorder (P = 0.056);Gain of disorder (P = 0.056);Gain of disorder (P = 0.056);Gain of disorder (P = 0.056);Gain of disorder (P = 0.056);Gain of disorder (P = 0.056);Gain of disorder (P = 0.056);Gain of disorder (P = 0.056);Gain of disorder (P = 0.056);Gain of disorder (P = 0.056);Gain of disorder (P = 0.056);Gain of disorder (P = 0.056);Gain of disorder (P = 0.056);Gain of disorder (P = 0.056);Gain of disorder (P = 0.056);Gain of disorder (P = 0.056);Gain of disorder (P = 0.056);.;
MVP		0.49
MPC		1.8
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.82
gMVP		0.94

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: rs2086875746; hg19: chr19-17873643;