5-73017237-T-C

Variant names:

• chr5-73017237-T-C
• rs1213229031
• NM_138782.3:c.725T>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_138782.3(FCHO2):​c.725T>C​(p.Met242Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000716 in 1,396,638 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: FCHO2 NM_138782.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.65

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FCHO2	NM_138782.3	c.725T>C	p.Met242Thr	missense_variant	Exon 8 of 26	ENST00000430046.7	NP_620137.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FCHO2	ENST00000430046.7	c.725T>C	p.Met242Thr	missense_variant	Exon 8 of 26	1	NM_138782.3	ENSP00000393776.2
FCHO2	ENST00000287761.7	c.725T>C	p.Met242Thr	missense_variant	Exon 8 of 11	1		ENSP00000287761.6
FCHO2	ENST00000512348.5	c.626T>C	p.Met209Thr	missense_variant	Exon 7 of 25	2		ENSP00000427296.1
FCHO2	ENST00000507345.6	c.650T>C	p.Met217Thr	missense_variant	Exon 7 of 7	5		ENSP00000426842.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.16e-7 AC: 1 AN: 1396638 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 689728

Gnomad4 AFR exome AF: 0.0000318

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 04, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.725T>C (p.M242T) alteration is located in exon 8 (coding exon 8) of the FCHO2 gene. This alteration results from a T to C substitution at nucleotide position 725, causing the methionine (M) at amino acid position 242 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	24
DANN	Benign	0.95
DEOGEN2	Benign	0.0046	T;T;.;T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.80	T;T;T;T
M_CAP	Benign	0.025	T
MetaRNN	Uncertain	0.46	T;T;T;T
MetaSVM	Benign	-0.57	T
MutationAssessor	Uncertain	2.1	M;.;.;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.5	N;.;N;N
REVEL	Benign	0.23
Sift	Benign	0.084	T;.;T;D
Sift4G	Benign	0.26	T;D;T;D
Polyphen		0.22	B;.;.;.
Vest4		0.63
MutPred		0.58		Loss of stability (P = 0.0421);.;.;Loss of stability (P = 0.0421);
MVP		0.47
MPC		0.37
ClinPred		0.25	T
GERP RS		5.5
Varity_R		0.62
gMVP		0.78

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

Publications

LitVar

Other links and lift over

dbSNP: rs1213229031; hg19: chr5-72313064;