Genetic Variant NM_138782.3:c.1357A>C (chr5-73063852-A-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_138782.3(FCHO2):c.1357A>C(p.Thr453Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000659 in 151,758 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. T453A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

FCHO2
NM_138782.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.10

Publications

1 publications found

Variant links:

Genes affected

FCHO2 (HGNC:25180): (FCH and mu domain containing endocytic adaptor 2) Enables identical protein binding activity. Involved in clathrin coat assembly and clathrin-dependent endocytosis. Located in clathrin-coated pit and clathrin-coated vesicle. [provided by Alliance of Genome Resources, Apr 2022]

FCHO2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2983292).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138782.3. 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
	FCHO2	NM_138782.3	MANE Select	c.1357A>C	p.Thr453Pro	missense	Exon 18 of 26	NP_620137.2	Q0JRZ9-1
	FCHO2	NM_001146032.2		c.1258A>C	p.Thr420Pro	missense	Exon 17 of 25	NP_001139504.1	Q0JRZ9-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FCHO2	ENST00000430046.7	TSL:1 MANE Select	c.1357A>C	p.Thr453Pro	missense	Exon 18 of 26	ENSP00000393776.2	Q0JRZ9-1
FCHO2	ENST00000956652.1		c.1357A>C	p.Thr453Pro	missense	Exon 18 of 27	ENSP00000626711.1
FCHO2	ENST00000956650.1		c.1387A>C	p.Thr463Pro	missense	Exon 19 of 27	ENSP00000626709.1

Frequencies

GnomAD3 genomes

AF:

0.00000659

AC:

AN:

151758

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000659

AC:

AN:

151758

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74096

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000242

AC:

AN:

41300

American (AMR)

AF:

0.00

AC:

AN:

15212

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4802

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10578

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67916

Other (OTH)

AF:

0.00

AC:

AN:

2086

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Uncertain

0.085

BayesDel_noAF

Benign

-0.12

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0085

Eigen

Uncertain

0.65

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.024

MetaRNN

Benign

0.30

MetaSVM

Benign

-0.95

MutationAssessor

Uncertain

2.9

PhyloP100

8.1

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-1.9

REVEL

Benign

0.21

Sift

Benign

0.25

Sift4G

Benign

0.13

Polyphen

1.0

Vest4

0.56

MutPred

0.15

Loss of phosphorylation at T453 (P = 0.0098)

MVP

0.43

MPC

1.0

ClinPred

0.99

GERP RS

5.6

Varity_R

0.39

gMVP

0.50

Mutation Taster

=38/62

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over