19-17762730-C-T

Variant names:

• chr19-17762730-C-T
• rs117245024
• ENST00000597512.1:n.28C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_015122.3(FCHO1):​c.28-32C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00548 in 1,503,916 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0032 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0057 (38 hom.)
• Consequence: FCHO1 NM_015122.3 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.140
• Publications: 1 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0048695803).
• BP6: Variant 19-17762730-C-T is Benign according to our data. Variant chr19-17762730-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2649554.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00317 (483/152280) while in subpopulation NFE AF = 0.00545 (371/68026). AF 95% confidence interval is 0.005. There are 1 homozygotes in GnomAd4. There are 214 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 38 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FCHO1	NM_015122.3	c.28-32C>T		intron_variant	Intron 4 of 28	ENST00000596536.6	NP_055937.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FCHO1	ENST00000596536.6	c.28-32C>T		intron_variant	Intron 4 of 28	5	NM_015122.3	ENSP00000470731.1
FCHO1	ENST00000699212.1	c.28-32C>T		intron_variant	Intron 4 of 29			ENSP00000514208.1
FCHO1	ENST00000594202.6	c.28-32C>T		intron_variant	Intron 4 of 28	5		ENSP00000473001.1
FCHO1	ENST00000596309.6	c.28-32C>T		intron_variant	Intron 4 of 28	4		ENSP00000470511.2
FCHO1	ENST00000596951.6	c.28-32C>T		intron_variant	Intron 4 of 28	5		ENSP00000472417.1
FCHO1	ENST00000600209.6	c.28-32C>T		intron_variant	Intron 4 of 28	5		ENSP00000469075.2
FCHO1	ENST00000600676.5	c.28-32C>T		intron_variant	Intron 3 of 27	2		ENSP00000470493.1
FCHO1	ENST00000699176.1	c.28-32C>T		intron_variant	Intron 4 of 28			ENSP00000514179.1
FCHO1	ENST00000699177.1	c.28-32C>T		intron_variant	Intron 4 of 28			ENSP00000514180.1
FCHO1	ENST00000699207.1	c.28-32C>T		intron_variant	Intron 4 of 28			ENSP00000514204.1
FCHO1	ENST00000699209.1	c.28-32C>T		intron_variant	Intron 4 of 28			ENSP00000514206.1
FCHO1	ENST00000699215.1	c.28-32C>T		intron_variant	Intron 3 of 27			ENSP00000514211.1
FCHO1	ENST00000699202.1	c.28-32C>T		intron_variant	Intron 4 of 28			ENSP00000514200.1
FCHO1	ENST00000699214.1	c.28-32C>T		intron_variant	Intron 3 of 27			ENSP00000514210.1
FCHO1	ENST00000699208.1	c.28-32C>T		intron_variant	Intron 4 of 27			ENSP00000514205.1
FCHO1	ENST00000699198.1	c.28-32C>T		intron_variant	Intron 4 of 28			ENSP00000514196.1
FCHO1	ENST00000699199.1	c.28-32C>T		intron_variant	Intron 3 of 27			ENSP00000514197.1
FCHO1	ENST00000699213.1	c.28-32C>T		intron_variant	Intron 3 of 27			ENSP00000514209.1
FCHO1	ENST00000699197.1	c.28-32C>T		intron_variant	Intron 4 of 27			ENSP00000514195.1
FCHO1	ENST00000699200.1	c.28-32C>T		intron_variant	Intron 4 of 27			ENSP00000514198.1
FCHO1	ENST00000699196.1	c.28-32C>T		intron_variant	Intron 4 of 26			ENSP00000514194.1
FCHO1	ENST00000699203.1	c.-123-32C>T		intron_variant	Intron 2 of 21			ENSP00000514201.1
FCHO1	ENST00000699201.1	n.28-32C>T		intron_variant	Intron 4 of 27			ENSP00000514199.1
FCHO1	ENST00000699205.1	n.28-32C>T		intron_variant	Intron 4 of 26			ENSP00000514202.1
FCHO1	ENST00000699206.1	n.28-32C>T		intron_variant	Intron 4 of 28			ENSP00000514203.1
FCHO1	ENST00000699210.1	n.28-32C>T		intron_variant	Intron 4 of 27			ENSP00000514207.1

Frequencies

GnomAD3 genomes AF: 0.00317 AC: 483 AN: 152162 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.00374

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00545

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00354 AC: 891 AN: 251360 AF XY: 0.00379

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.00217

Gnomad ASJ exome AF: 0.00357

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.00546

Gnomad OTH exome AF: 0.00375

GnomAD4 exome AF: 0.00574 AC: 7758 AN: 1351636 Hom.: 38 Cov.: 22 AF XY: 0.00578 AC XY: 3926 AN XY: 678988

African (AFR) AF: 0.00105 AC: 33 AN: 31382

American (AMR) AF: 0.00211 AC: 94 AN: 44592

Ashkenazi Jewish (ASJ) AF: 0.00400 AC: 102 AN: 25494

East Asian (EAS) AF: 0.0000256 AC: 1 AN: 39100

South Asian (SAS) AF: 0.00350 AC: 294 AN: 84120

European-Finnish (FIN) AF: 0.000487 AC: 26 AN: 53372

Middle Eastern (MID) AF: 0.00451 AC: 25 AN: 5542

European-Non Finnish (NFE) AF: 0.00679 AC: 6862 AN: 1011304

Other (OTH) AF: 0.00566 AC: 321 AN: 56730

GnomAD4 genome AF: 0.00317 AC: 483 AN: 152280 Hom.: 1 Cov.: 31 AF XY: 0.00287 AC XY: 214 AN XY: 74450

African (AFR) AF: 0.000963 AC: 40 AN: 41558

American (AMR) AF: 0.00236 AC: 36 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00374 AC: 13 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00332 AC: 16 AN: 4826

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00545 AC: 371 AN: 68026

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.00338 Hom.: 0

Bravo AF: 0.00361

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00571 AC: 22

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00581 AC: 50

ExAC AF: 0.00355 AC: 431

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00725

EpiControl AF: 0.00658

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jan 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

FCHO1: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	0.90
DANN	Benign	0.79
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.35	T
M_CAP	Benign	0.00066	T
MetaRNN	Benign	0.0049	T
PhyloP100		-0.14
Sift4G	Benign	0.44	T
Vest4		0.13
MVP		0.35
GERP RS		0.84
PromoterAI		0.052	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Mutation Taster		=100/0	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: rs117245024; hg19: chr19-17873539;