5-115543054-C-T

Position:

• chr5-115543054-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_020177.3(FEM1C):​c.440G>A​(p.Arg147Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FEM1C NM_020177.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.90

Genes affected

FEM1C (HGNC:16933): (fem-1 homolog C) Enables ubiquitin ligase-substrate adaptor activity. Involved in ubiquitin-dependent protein catabolic process via the C-end degron rule pathway. Located in cytosol and nucleoplasm. Part of Cul2-RING ubiquitin ligase complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), FEM1C. . Gene score misZ 2.4311 (greater than the threshold 3.09). Trascript score misZ 3.3305 (greater than threshold 3.09). GenCC has associacion of gene with complex neurodevelopmental disorder.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.763

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FEM1C	NM_020177.3	c.440G>A	p.Arg147Gln	missense_variant	2/3	ENST00000274457.5	NP_064562.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FEM1C	ENST00000274457.5	c.440G>A	p.Arg147Gln	missense_variant	2/3	1	NM_020177.3	ENSP00000274457	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 06, 2023

The c.440G>A (p.R147Q) alteration is located in exon 2 (coding exon 1) of the FEM1C gene. This alteration results from a G to A substitution at nucleotide position 440, causing the arginine (R) at amino acid position 147 to be replaced by a glutamine (Q). 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	Pathogenic	0.82
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.16	T
Eigen	Uncertain	0.64
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.051	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	0.94	L
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.40
Sift	Benign	0.052	T
Sift4G	Benign	0.13	T
Polyphen		1.0	D
Vest4		0.68
MutPred		0.48		Loss of stability (P = 0.0906);
MVP		0.64
MPC		1.3
ClinPred		0.99	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.69
gMVP		0.63

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-114878751;