rs531313433

Variant names:

• chr5-73017229-A-G
• rs531313433
• NM_138782.3:c.717A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_138782.3(FCHO2):​c.717A>G​(p.Ile239Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000104 in 1,540,706 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: FCHO2 NM_138782.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.600
• Publications: 0 publications found

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]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.05545348).
• BS2: High AC in GnomAdExome4 at 15 AD gene.

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.717A>G	p.Ile239Met	missense	Exon 8 of 26	NP_620137.2	Q0JRZ9-1
	FCHO2	NM_001146032.2		c.618A>G	p.Ile206Met	missense	Exon 7 of 25	NP_001139504.1	Q0JRZ9-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FCHO2	ENST00000430046.7	TSL:1 MANE Select	c.717A>G	p.Ile239Met	missense	Exon 8 of 26	ENSP00000393776.2	Q0JRZ9-1
	FCHO2	ENST00000287761.7	TSL:1	c.717A>G	p.Ile239Met	missense	Exon 8 of 11	ENSP00000287761.6	H7BXJ4
	FCHO2	ENST00000956652.1		c.717A>G	p.Ile239Met	missense	Exon 8 of 27	ENSP00000626711.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152240 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000249 AC: 4 AN: 160686 AF XY: 0.0000236

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000108 AC: 15 AN: 1388348 Hom.: 0 Cov.: 27 AF XY: 0.0000146 AC XY: 10 AN XY: 685370

African (AFR) AF: 0.00 AC: 0 AN: 31026

American (AMR) AF: 0.00 AC: 0 AN: 34276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24786

East Asian (EAS) AF: 0.00 AC: 0 AN: 35998

South Asian (SAS) AF: 0.000199 AC: 15 AN: 75424

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49566

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5644

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1073990

Other (OTH) AF: 0.00 AC: 0 AN: 57638

GnomAD4 genome AF: 0.00000656 AC: 1 AN: 152358 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74520

African (AFR) AF: 0.00 AC: 0 AN: 41590

American (AMR) AF: 0.00 AC: 0 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2116

ExAC AF: 0.0000342 AC: 4

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	21
DANN	Benign	0.85
DEOGEN2	Benign	0.0027	T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.055	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.60
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	0.29	N
REVEL	Benign	0.056
Sift	Benign	0.057	T
Sift4G	Benign	0.11	T
Polyphen		0.0	B
Vest4		0.24
MutPred		0.31		Gain of disorder (P = 0.0584)
MVP		0.33
MPC		0.25
ClinPred		0.073	T
GERP RS		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.29
gMVP		0.43
Mutation Taster		=60/40	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: rs531313433; hg19: chr5-72313056;