5-115543118-C-T

Variant names:

• chr5-115543118-C-T
• NM_020177.3:c.376G>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM5

The NM_020177.3(FEM1C):​c.376G>A​(p.Asp126Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. D126H) has been classified as Likely pathogenic.

• 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-115543118-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2504571.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FEM1C	NM_020177.3	c.376G>A	p.Asp126Asn	missense_variant	Exon 2 of 3	ENST00000274457.5	NP_064562.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FEM1C	ENST00000274457.5	c.376G>A	p.Asp126Asn	missense_variant	Exon 2 of 3	1	NM_020177.3	ENSP00000274457.3

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 provided Uncertain:1

Oct 11, 2022

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The FEM1C c.376G>A (p.Asp126Asn) missense variant results in the substitution of aspartic acid at amino acid position 126 with asparagine. To our knowledge, this variant has not been reported in the peer-reviewed literature. However, in both reported individuals with candidate variants in FEM1C, a different amino acid change at Asp126 was reported, specifically c.376G>C; (p.Asp126His) and c.377A>T (p.Asp126Val) (PMID: 28135719; https://doi.org/10.1101/2022.04.24.489208). This variant is not found in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Asp126 is a highly conserved residue located in the degron binding pocket of the protein and has been shown to interact directly with terminal arginines in arg/C-degrons (PMID: 33398168; PMID: 33398170). Based on the available evidence, the c.376G>A (p.Asp126Asn) variant is classified as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Benign	-0.091	T
BayesDel_noAF	Benign	-0.37
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.20
Eigen_PC	Benign	0.086
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.037	D
MetaRNN	Uncertain	0.46	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-0.92	N
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-4.1	D
REVEL	Benign	0.28
Sift	Uncertain	0.022	D
Sift4G	Benign	0.064	T
Polyphen		0.31	B
Vest4		0.67
MutPred		0.52		Gain of methylation at R121 (P = 0.1107);
MVP		0.32
MPC		0.84
ClinPred		0.99	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.61
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-114878815;