19-17762799-G-C

Variant names:

• chr19-17762799-G-C
• rs1323439763
• NM_015122.3:c.65G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015122.3(FCHO1):​c.65G>C​(p.Ser22Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S22N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: FCHO1 NM_015122.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.65
• 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: ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20027173).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FCHO1	NM_015122.3	c.65G>C	p.Ser22Thr	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.65G>C	p.Ser22Thr	missense_variant	Exon 5 of 29	5	NM_015122.3	ENSP00000470731.1
FCHO1	ENST00000699212.1	c.65G>C	p.Ser22Thr	missense_variant	Exon 5 of 30			ENSP00000514208.1
FCHO1	ENST00000594202.6	c.65G>C	p.Ser22Thr	missense_variant	Exon 5 of 29	5		ENSP00000473001.1
FCHO1	ENST00000596309.6	c.65G>C	p.Ser22Thr	missense_variant	Exon 5 of 29	4		ENSP00000470511.2
FCHO1	ENST00000596951.6	c.65G>C	p.Ser22Thr	missense_variant	Exon 5 of 29	5		ENSP00000472417.1
FCHO1	ENST00000600209.6	c.65G>C	p.Ser22Thr	missense_variant	Exon 5 of 29	5		ENSP00000469075.2
FCHO1	ENST00000600676.5	c.65G>C	p.Ser22Thr	missense_variant	Exon 4 of 28	2		ENSP00000470493.1
FCHO1	ENST00000699176.1	c.65G>C	p.Ser22Thr	missense_variant	Exon 5 of 29			ENSP00000514179.1
FCHO1	ENST00000699177.1	c.65G>C	p.Ser22Thr	missense_variant	Exon 5 of 29			ENSP00000514180.1
FCHO1	ENST00000699207.1	c.65G>C	p.Ser22Thr	missense_variant	Exon 5 of 29			ENSP00000514204.1
FCHO1	ENST00000699209.1	c.65G>C	p.Ser22Thr	missense_variant	Exon 5 of 29			ENSP00000514206.1
FCHO1	ENST00000699215.1	c.65G>C	p.Ser22Thr	missense_variant	Exon 4 of 28			ENSP00000514211.1
FCHO1	ENST00000699202.1	c.65G>C	p.Ser22Thr	missense_variant	Exon 5 of 29			ENSP00000514200.1
FCHO1	ENST00000699214.1	c.65G>C	p.Ser22Thr	missense_variant	Exon 4 of 28			ENSP00000514210.1
FCHO1	ENST00000699208.1	c.65G>C	p.Ser22Thr	missense_variant	Exon 5 of 28			ENSP00000514205.1
FCHO1	ENST00000699198.1	c.65G>C	p.Ser22Thr	missense_variant	Exon 5 of 29			ENSP00000514196.1
FCHO1	ENST00000699199.1	c.65G>C	p.Ser22Thr	missense_variant	Exon 4 of 28			ENSP00000514197.1
FCHO1	ENST00000699213.1	c.65G>C	p.Ser22Thr	missense_variant	Exon 4 of 28			ENSP00000514209.1
FCHO1	ENST00000699197.1	c.65G>C	p.Ser22Thr	missense_variant	Exon 5 of 28			ENSP00000514195.1
FCHO1	ENST00000699200.1	c.65G>C	p.Ser22Thr	missense_variant	Exon 5 of 28			ENSP00000514198.1
FCHO1	ENST00000699196.1	c.65G>C	p.Ser22Thr	missense_variant	Exon 5 of 27			ENSP00000514194.1
FCHO1	ENST00000699201.1	n.65G>C		non_coding_transcript_exon_variant	Exon 5 of 28			ENSP00000514199.1
FCHO1	ENST00000699205.1	n.65G>C		non_coding_transcript_exon_variant	Exon 5 of 27			ENSP00000514202.1
FCHO1	ENST00000699206.1	n.65G>C		non_coding_transcript_exon_variant	Exon 5 of 29			ENSP00000514203.1
FCHO1	ENST00000699210.1	n.65G>C		non_coding_transcript_exon_variant	Exon 5 of 28			ENSP00000514207.1
FCHO1	ENST00000699203.1	c.-86G>C		5_prime_UTR_variant	Exon 3 of 22			ENSP00000514201.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000660 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.035	T;T;T;T;T;.;T;T;T;T;T;.;.;.;T;T;.;T;T;T;.
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.0070
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.71	T;T;.;T;T;T;T;T;.;T;T;T;T;T;T;T;T;T;.;T;T
M_CAP	Benign	0.0095	T
MetaRNN	Benign	0.20	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	1.6	.;L;L;.;.;.;.;.;L;.;.;.;.;.;.;.;.;.;L;.;.
PhyloP100		4.6
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.1	.;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Benign	0.053
Sift	Benign	0.062	.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.12	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0010	.;B;B;.;.;.;.;.;B;.;.;.;.;.;.;.;.;.;B;.;.
Vest4		0.21
MutPred		0.56		Loss of disorder (P = 0.103);Loss of disorder (P = 0.103);Loss of disorder (P = 0.103);Loss of disorder (P = 0.103);Loss of disorder (P = 0.103);Loss of disorder (P = 0.103);Loss of disorder (P = 0.103);Loss of disorder (P = 0.103);Loss of disorder (P = 0.103);Loss of disorder (P = 0.103);Loss of disorder (P = 0.103);Loss of disorder (P = 0.103);Loss of disorder (P = 0.103);Loss of disorder (P = 0.103);Loss of disorder (P = 0.103);Loss of disorder (P = 0.103);Loss of disorder (P = 0.103);Loss of disorder (P = 0.103);Loss of disorder (P = 0.103);Loss of disorder (P = 0.103);.;
MVP		0.13
MPC		0.55
ClinPred		0.68	D
GERP RS		3.5
PromoterAI		-0.011	Neutral
Varity_R		0.075
gMVP		0.64
Mutation Taster		=93/7	polymorphism

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: rs1323439763; hg19: chr19-17873608;