Genetic Variant FCHO1:n.56G>C (chr19-17762758-G-C) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS1

The NM_015122.3(FCHO1):c.28-4G>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000151 in 1,457,274 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.000015 ( 1 hom. )

Consequence

FCHO1
NM_015122.3 splice_region, intron

Scores

Splicing: ADA: 0.000007402

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.233

Publications

0 publications found

Variant links:

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)

FCHO1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.78).

BS1

Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.0000151 (22/1457274) while in subpopulation EAS AF = 0.000529 (21/39668). AF 95% confidence interval is 0.000355. There are 1 homozygotes in GnomAdExome4. There are 11 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FCHO1	NM_015122.3 link	c.28-4G>C		splice_region_variant, intron_variant	Intron 4 of 28	ENST00000596536.6	NP_055937.1	O14526-1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
FCHO1	ENST00000596536.6 link	c.28-4G>C	splice_region_variant, intron_variant	Intron 4 of 28	5	NM_015122.3	ENSP00000470731.1	O14526-1
FCHO1	ENST00000699212.1 link	c.28-4G>C	splice_region_variant, intron_variant	Intron 4 of 29			ENSP00000514208.1	A0A8V8TPN1
FCHO1	ENST00000594202.6 link	c.28-4G>C	splice_region_variant, intron_variant	Intron 4 of 28	5		ENSP00000473001.1	A0A0C3SFZ9
FCHO1	ENST00000596309.6 link	c.28-4G>C	splice_region_variant, intron_variant	Intron 4 of 28	4		ENSP00000470511.2	O14526-1M0QZF0
FCHO1	ENST00000596951.6 link	c.28-4G>C	splice_region_variant, intron_variant	Intron 4 of 28	5		ENSP00000472417.1	O14526-1
FCHO1	ENST00000600209.6 link	c.28-4G>C	splice_region_variant, intron_variant	Intron 4 of 28	5		ENSP00000469075.2	O14526-1M0QXD1
FCHO1	ENST00000600676.5 link	c.28-4G>C	splice_region_variant, intron_variant	Intron 3 of 27	2		ENSP00000470493.1	O14526-1
FCHO1	ENST00000699176.1 link	c.28-4G>C	splice_region_variant, intron_variant	Intron 4 of 28			ENSP00000514179.1	O14526-1
FCHO1	ENST00000699177.1 link	c.28-4G>C	splice_region_variant, intron_variant	Intron 4 of 28			ENSP00000514180.1	O14526-1
FCHO1	ENST00000699207.1 link	c.28-4G>C	splice_region_variant, intron_variant	Intron 4 of 28			ENSP00000514204.1	O14526-1
FCHO1	ENST00000699209.1 link	c.28-4G>C	splice_region_variant, intron_variant	Intron 4 of 28			ENSP00000514206.1	O14526-1
FCHO1	ENST00000699215.1 link	c.28-4G>C	splice_region_variant, intron_variant	Intron 3 of 27			ENSP00000514211.1	O14526-1
FCHO1	ENST00000699202.1 link	c.28-4G>C	splice_region_variant, intron_variant	Intron 4 of 28			ENSP00000514200.1	A0A8V8TMX9
FCHO1	ENST00000699214.1 link	c.28-4G>C	splice_region_variant, intron_variant	Intron 3 of 27			ENSP00000514210.1	A0A8V8TMX9
FCHO1	ENST00000699208.1 link	c.28-4G>C	splice_region_variant, intron_variant	Intron 4 of 27			ENSP00000514205.1	A0A8V8TPA0
FCHO1	ENST00000699198.1 link	c.28-4G>C	splice_region_variant, intron_variant	Intron 4 of 28			ENSP00000514196.1	M0QYA9
FCHO1	ENST00000699199.1 link	c.28-4G>C	splice_region_variant, intron_variant	Intron 3 of 27			ENSP00000514197.1	M0QYA9
FCHO1	ENST00000699213.1 link	c.28-4G>C	splice_region_variant, intron_variant	Intron 3 of 27			ENSP00000514209.1	M0QYA9
FCHO1	ENST00000699197.1 link	c.28-4G>C	splice_region_variant, intron_variant	Intron 4 of 27			ENSP00000514195.1	A0A8V8TNC3
FCHO1	ENST00000699200.1 link	c.28-4G>C	splice_region_variant, intron_variant	Intron 4 of 27			ENSP00000514198.1	A0A8V8TNC3
FCHO1	ENST00000699196.1 link	c.28-4G>C	splice_region_variant, intron_variant	Intron 4 of 26			ENSP00000514194.1	A0A8V8TP91
FCHO1	ENST00000699203.1 link	c.-123-4G>C	splice_region_variant, intron_variant	Intron 2 of 21			ENSP00000514201.1	A0A8V8TPM7
FCHO1	ENST00000699201.1 link	n.28-4G>C	splice_region_variant, intron_variant	Intron 4 of 27			ENSP00000514199.1	A0A8V8TP96
FCHO1	ENST00000699205.1 link	n.28-4G>C	splice_region_variant, intron_variant	Intron 4 of 26			ENSP00000514202.1	A0A8V8TMV7
FCHO1	ENST00000699206.1 link	n.28-4G>C	splice_region_variant, intron_variant	Intron 4 of 28			ENSP00000514203.1	A0A8V8TMV7
FCHO1	ENST00000699210.1 link	n.28-4G>C	splice_region_variant, intron_variant	Intron 4 of 27			ENSP00000514207.1	A0A8V8TND1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.0000151

AC:

AN:

1457274

Hom.:

Cov.:

AF XY:

0.0000152

AC XY:

AN XY:

725430

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33374

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26114

East Asian (EAS)

AF:

0.000529

AC:

AN:

39668

South Asian (SAS)

AF:

0.00

AC:

AN:

86170

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1107814

Other (OTH)

AF:

0.0000166

AC:

AN:

60242

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.520

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

3.8

(source)

DANN

Benign

0.72

PhyloP100

-0.23

PromoterAI

-0.0068

Neutral

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0000074

dbscSNV1_RF

Benign

0.0

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

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19-17762758-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over