rs375969109

Variant names:

• chr5-73063852-A-C
• rs375969109
• NM_138782.3:c.1357A>C

Your query was ambiguous. Multiple possible variants found:

• chr5-73063852-A-C
• chr5-73063852-A-G
• chr5-73063852-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.10

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2983292).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FCHO2	NM_138782.3	c.1357A>C	p.Thr453Pro	missense_variant	Exon 18 of 26	ENST00000430046.7	NP_620137.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FCHO2	ENST00000430046.7	c.1357A>C	p.Thr453Pro	missense_variant	Exon 18 of 26	1	NM_138782.3	ENSP00000393776.2
FCHO2	ENST00000512348.5	c.1258A>C	p.Thr420Pro	missense_variant	Exon 17 of 25	2		ENSP00000427296.1
FCHO2	ENST00000508431.1	n.116A>C		non_coding_transcript_exon_variant	Exon 2 of 5	4

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151758 Hom.: 0 Cov.: 32

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.: 30

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151758 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74096

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.085	D
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0085	T;.
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.30	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.9	M;.
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.9	N;D
REVEL	Benign	0.21
Sift	Benign	0.25	T;T
Sift4G	Benign	0.13	T;T
Polyphen		1.0	D;.
Vest4		0.56
MutPred		0.15		Loss of phosphorylation at T453 (P = 0.0098);.;
MVP		0.43
MPC		1.0
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.39
gMVP		0.50

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

LitVar

Other links and lift over

dbSNP: rs375969109; hg19: chr5-72359679;