NM_015122.3:c.40C>A

Variant names:

• chr19-17762774-C-A
• rs779934590
• NM_015122.3:c.40C>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015122.3(FCHO1):​c.40C>A​(p.His14Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,248 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FCHO1 NM_015122.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.13

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12999824).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FCHO1	NM_015122.3	c.40C>A	p.His14Asn	missense_variant	Exon 5 of 29	ENST00000596536.6	NP_055937.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FCHO1	ENST00000596536.6	c.40C>A	p.His14Asn	missense_variant	Exon 5 of 29	5	NM_015122.3	ENSP00000470731.1
FCHO1	ENST00000699212.1	c.40C>A	p.His14Asn	missense_variant	Exon 5 of 30			ENSP00000514208.1
FCHO1	ENST00000594202.6	c.40C>A	p.His14Asn	missense_variant	Exon 5 of 29	5		ENSP00000473001.1
FCHO1	ENST00000596309.6	c.40C>A	p.His14Asn	missense_variant	Exon 5 of 29	4		ENSP00000470511.2
FCHO1	ENST00000596951.6	c.40C>A	p.His14Asn	missense_variant	Exon 5 of 29	5		ENSP00000472417.1
FCHO1	ENST00000600209.6	c.40C>A	p.His14Asn	missense_variant	Exon 5 of 29	5		ENSP00000469075.2
FCHO1	ENST00000600676.5	c.40C>A	p.His14Asn	missense_variant	Exon 4 of 28	2		ENSP00000470493.1
FCHO1	ENST00000699176.1	c.40C>A	p.His14Asn	missense_variant	Exon 5 of 29			ENSP00000514179.1
FCHO1	ENST00000699177.1	c.40C>A	p.His14Asn	missense_variant	Exon 5 of 29			ENSP00000514180.1
FCHO1	ENST00000699207.1	c.40C>A	p.His14Asn	missense_variant	Exon 5 of 29			ENSP00000514204.1
FCHO1	ENST00000699209.1	c.40C>A	p.His14Asn	missense_variant	Exon 5 of 29			ENSP00000514206.1
FCHO1	ENST00000699215.1	c.40C>A	p.His14Asn	missense_variant	Exon 4 of 28			ENSP00000514211.1
FCHO1	ENST00000699202.1	c.40C>A	p.His14Asn	missense_variant	Exon 5 of 29			ENSP00000514200.1
FCHO1	ENST00000699214.1	c.40C>A	p.His14Asn	missense_variant	Exon 4 of 28			ENSP00000514210.1
FCHO1	ENST00000699208.1	c.40C>A	p.His14Asn	missense_variant	Exon 5 of 28			ENSP00000514205.1
FCHO1	ENST00000699198.1	c.40C>A	p.His14Asn	missense_variant	Exon 5 of 29			ENSP00000514196.1
FCHO1	ENST00000699199.1	c.40C>A	p.His14Asn	missense_variant	Exon 4 of 28			ENSP00000514197.1
FCHO1	ENST00000699213.1	c.40C>A	p.His14Asn	missense_variant	Exon 4 of 28			ENSP00000514209.1
FCHO1	ENST00000699197.1	c.40C>A	p.His14Asn	missense_variant	Exon 5 of 28			ENSP00000514195.1
FCHO1	ENST00000699200.1	c.40C>A	p.His14Asn	missense_variant	Exon 5 of 28			ENSP00000514198.1
FCHO1	ENST00000699196.1	c.40C>A	p.His14Asn	missense_variant	Exon 5 of 27			ENSP00000514194.1
FCHO1	ENST00000699203	c.-111C>A		5_prime_UTR_variant	Exon 3 of 22			ENSP00000514201.1
FCHO1	ENST00000699201.1	n.40C>A		non_coding_transcript_exon_variant	Exon 5 of 28			ENSP00000514199.1
FCHO1	ENST00000699205.1	n.40C>A		non_coding_transcript_exon_variant	Exon 5 of 27			ENSP00000514202.1
FCHO1	ENST00000699206.1	n.40C>A		non_coding_transcript_exon_variant	Exon 5 of 29			ENSP00000514203.1
FCHO1	ENST00000699210.1	n.40C>A		non_coding_transcript_exon_variant	Exon 5 of 28			ENSP00000514207.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251458 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135900

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461248 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726974

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Sep 02, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces histidine with asparagine at codon 14 of the FCHO1 protein (p.His14Asn). The histidine residue is moderately conserved and there is a small physicochemical difference between histidine and asparagine. This variant is present in population databases (rs779934590, ExAC 0.001%). This variant has not been reported in the literature in individuals affected with FCHO1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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	0.084
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Uncertain	25
DANN	Benign	0.90
DEOGEN2	Benign	0.0029	T;T;T;T;T;.;T;T;T;T;T;.;.;.;T;T;T;.;T;T;T;.
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.74	T;T;.;T;T;T;D;T;.;T;T;T;T;T;T;T;.;T;T;.;T;T
M_CAP	Benign	0.0072	T
MetaRNN	Benign	0.13	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.66	.;N;N;.;.;.;.;.;N;.;.;.;.;.;.;.;.;.;.;N;.;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.67	.;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Benign	0.082
Sift	Benign	1.0	.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.76	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;.;T;T;T;T;T
Polyphen		0.95	.;P;P;.;.;.;.;.;P;.;.;.;.;.;.;.;.;.;.;P;.;.
Vest4		0.25
MutPred		0.45		Gain of ubiquitination at K12 (P = 0.0743);Gain of ubiquitination at K12 (P = 0.0743);Gain of ubiquitination at K12 (P = 0.0743);Gain of ubiquitination at K12 (P = 0.0743);Gain of ubiquitination at K12 (P = 0.0743);Gain of ubiquitination at K12 (P = 0.0743);Gain of ubiquitination at K12 (P = 0.0743);Gain of ubiquitination at K12 (P = 0.0743);Gain of ubiquitination at K12 (P = 0.0743);Gain of ubiquitination at K12 (P = 0.0743);Gain of ubiquitination at K12 (P = 0.0743);Gain of ubiquitination at K12 (P = 0.0743);Gain of ubiquitination at K12 (P = 0.0743);Gain of ubiquitination at K12 (P = 0.0743);Gain of ubiquitination at K12 (P = 0.0743);Gain of ubiquitination at K12 (P = 0.0743);Gain of ubiquitination at K12 (P = 0.0743);Gain of ubiquitination at K12 (P = 0.0743);Gain of ubiquitination at K12 (P = 0.0743);Gain of ubiquitination at K12 (P = 0.0743);Gain of ubiquitination at K12 (P = 0.0743);.;
MVP		0.24
MPC		0.74
ClinPred		0.38	T
GERP RS		4.7
Varity_R		0.14
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

Other links and lift over

dbSNP: rs779934590; hg19: chr19-17873583;