19-17762834-G-C

Variant names:

• chr19-17762834-G-C
• rs2086875746
• NM_015122.3:c.100G>C

Variant summary

Our verdict is Uncertain significance. The variant received 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A34T) has been classified as Uncertain significance.

• 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
• 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: Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 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 VariationId is 805884.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015122.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FCHO1	NM_015122.3	MANE Select	c.100G>C	p.Ala34Pro	missense	Exon 5 of 29	NP_055937.1	O14526-1
	FCHO1	NM_001161357.2		c.100G>C	p.Ala34Pro	missense	Exon 5 of 29	NP_001154829.1	A0A0C3SFZ9
	FCHO1	NM_001161358.2		c.100G>C	p.Ala34Pro	missense	Exon 4 of 28	NP_001154830.1	O14526-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FCHO1	ENST00000596536.6	TSL:5 MANE Select	c.100G>C	p.Ala34Pro	missense	Exon 5 of 29	ENSP00000470731.1	O14526-1
	FCHO1	ENST00000699212.1		c.100G>C	p.Ala34Pro	missense	Exon 5 of 30	ENSP00000514208.1	A0A8V8TPN1
	FCHO1	ENST00000594202.6	TSL:5	c.100G>C	p.Ala34Pro	missense	Exon 5 of 29	ENSP00000473001.1	A0A0C3SFZ9

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Immunodeficiency 76 (1)
1	-	-	Severe congenital neutropenia (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.057	D
MetaRNN	Uncertain	0.69	D
MetaSVM	Benign	-0.81	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		3.4
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.36
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.74
MutPred		0.68		Gain of disorder (P = 0.056)
MVP		0.49
MPC		1.8
ClinPred		1.0	D
GERP RS		4.6
PromoterAI		0.041	Neutral
Varity_R		0.82
gMVP		0.94
Mutation Taster		=0/100	disease causing (ClinVar)

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: rs2086875746; hg19: chr19-17873643;