NM_020177.3:c.376G>C

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PS1_Moderate PM2 PP3 PP5_Moderate

The NM_020177.3(FEM1C):​c.376G>C​(p.Asp126His) 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 Likely pathogenic (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D126N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FEM1C NM_020177.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1 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 Likely_pathogenic. Variant got 7 ACMG points.

• PS1: Transcript NM_020177.3 (FEM1C) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.759
• PP5: Variant 5-115543118-C-G is Pathogenic according to our data. 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>C	p.Asp126His	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>C	p.Asp126His	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: Likely pathogenic

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neurodevelopmental disorder Pathogenic:1

Oct 10, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as Likely pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from aspartic acid to histidine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (v2, v3 and v4). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. p.(Asp126Val) has been reported de novo in an individual with an uncharacterised developmental disorder (PMID: 28135719). p.(Asp126Asn) has also been reported as a VUS (ClinVar). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in an unrelated individual. This variant has been reported de novo in an individual with severe developmental delay, absent speech, pyramidal signs and limb ataxia (PMID: 36336956). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. The equivalent variant introduced into the nematode C.elegans resulted in impaired locomotion suggested to be caused by synaptic abnormalities rather than muscle dysfunction (PMID: 36336956). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided Uncertain:1

Jun 06, 2023

OMIM

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.044	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	-0.81	N
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-5.6	D
REVEL	Uncertain	0.59
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.069	T
Polyphen		1.0	D
Vest4		0.76
MutPred		0.51		Gain of methylation at R121 (P = 0.1136);
MVP		0.79
MPC		1.4
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.83
gMVP		0.83

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;