5-115543305-T-A

Position:

• chr5-115543305-T-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2 PP2 BP4_Strong

The NM_020177.3(FEM1C):​c.189A>T​(p.Gln63His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign 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: 0.222

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_benign. Variant got -1 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.038749963).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FEM1C	NM_020177.3	c.189A>T	p.Gln63His	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.189A>T	p.Gln63His	missense_variant	2/3	1	NM_020177.3	ENSP00000274457	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

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

May 09, 2023

The c.189A>T (p.Q63H) alteration is located in exon 2 (coding exon 1) of the FEM1C gene. This alteration results from a A to T substitution at nucleotide position 189, causing the glutamine (Q) at amino acid position 63 to be replaced by a histidine (H). 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	Benign	0.085
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	14
DANN	Benign	0.76
DEOGEN2	Benign	0.036	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.0064	T
MetaRNN	Benign	0.039	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.89	N
MutationTaster	Benign	0.98	D
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.62	N
REVEL	Benign	0.12
Sift	Benign	0.28	T
Sift4G	Benign	0.45	T
Polyphen		0.0	B
Vest4		0.11
MutPred		0.48		Gain of loop (P = 0.1069);
MVP		0.21
MPC		0.52
ClinPred		0.17	T
GERP RS		-0.86
Varity_R		0.22
gMVP		0.53

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: chr5-114879002;