NM_138782.3:c.943A>T

Variant names:

• chr5-73051352-A-T
• rs774230768
• NM_138782.3:c.943A>T

Variant summary

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

The NM_138782.3(FCHO2):​c.943A>T​(p.Ile315Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000021 in 1,527,166 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I315V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000019 (1 hom.)
• Consequence: FCHO2 NM_138782.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.83
• 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=0.013338417).
• BS2: High AC in GnomAd4 at 6 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.943A>T	p.Ile315Phe	missense	Exon 12 of 26	NP_620137.2	Q0JRZ9-1
	FCHO2	NM_001146032.2		c.844A>T	p.Ile282Phe	missense	Exon 11 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.943A>T	p.Ile315Phe	missense	Exon 12 of 26	ENSP00000393776.2	Q0JRZ9-1
	FCHO2	ENST00000956652.1		c.943A>T	p.Ile315Phe	missense	Exon 12 of 27	ENSP00000626711.1
	FCHO2	ENST00000956650.1		c.943A>T	p.Ile315Phe	missense	Exon 12 of 27	ENSP00000626709.1

Frequencies

GnomAD3 genomes AF: 0.0000395 AC: 6 AN: 151980 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

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: 0.000479

GnomAD2 exomes AF: 0.000133 AC: 20 AN: 150200 AF XY: 0.000176

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000755

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000168

Gnomad OTH exome AF: 0.000471

GnomAD4 exome AF: 0.0000189 AC: 26 AN: 1375186 Hom.: 1 Cov.: 27 AF XY: 0.0000221 AC XY: 15 AN XY: 678988

African (AFR) AF: 0.00 AC: 0 AN: 30526

American (AMR) AF: 0.000537 AC: 18 AN: 33496

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24904

East Asian (EAS) AF: 0.00 AC: 0 AN: 35374

South Asian (SAS) AF: 0.00 AC: 0 AN: 76818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49116

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5636

European-Non Finnish (NFE) AF: 0.00000471 AC: 5 AN: 1062200

Other (OTH) AF: 0.0000525 AC: 3 AN: 57116

GnomAD4 genome AF: 0.0000395 AC: 6 AN: 151980 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74232

African (AFR) AF: 0.00 AC: 0 AN: 41368

American (AMR) AF: 0.000328 AC: 5 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10560

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67998

Other (OTH) AF: 0.000479 AC: 1 AN: 2086

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000529

ExAC AF: 0.0000260 AC: 2

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	0.12
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	21
DANN	Uncertain	0.97
DEOGEN2	Benign	0.0052	T
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.021
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.0056	T
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L
PhyloP100		2.8
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.86	N
REVEL	Benign	0.041
Sift	Benign	0.74	T
Sift4G	Benign	0.71	T
Polyphen		0.0010	B
Vest4		0.099
MutPred		0.26		Gain of catalytic residue at I315 (P = 0.2818)
MVP		0.19
MPC		0.38
ClinPred		0.055	T
GERP RS		4.9
Varity_R		0.088
gMVP		0.088
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs774230768; hg19: chr5-72347179;