19-17762834-G-A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2 PM5 BP4

The NM_015122.3(FCHO1):​c.100G>A​(p.Ala34Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 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. A34P) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: FCHO1 NM_015122.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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
• PM5: Other missense variant is known to change same aminoacid residue: 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.39104515).

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>A	p.Ala34Thr	missense	Exon 5 of 29	NP_055937.1	O14526-1
	FCHO1	NM_001161357.2		c.100G>A	p.Ala34Thr	missense	Exon 5 of 29	NP_001154829.1	A0A0C3SFZ9
	FCHO1	NM_001161358.2		c.100G>A	p.Ala34Thr	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>A	p.Ala34Thr	missense	Exon 5 of 29	ENSP00000470731.1	O14526-1
	FCHO1	ENST00000699212.1		c.100G>A	p.Ala34Thr	missense	Exon 5 of 30	ENSP00000514208.1	A0A8V8TPN1
	FCHO1	ENST00000594202.6	TSL:5	c.100G>A	p.Ala34Thr	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: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.034	T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.39	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L
PhyloP100		3.4
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.18
Sift	Uncertain	0.027	D
Sift4G	Benign	0.096	T
Polyphen		1.0	D
Vest4		0.25
MutPred		0.51		Loss of stability (P = 0.0696)
MVP		0.37
MPC		1.6
ClinPred		0.99	D
GERP RS		4.6
PromoterAI		0.072	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.34
gMVP		0.76
Mutation Taster		=30/70	disease causing

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;