rs748705585

Variant names:

• chr5-115525024-C-A
• rs748705585
• NM_020177.3:c.1138G>T

Your query was ambiguous. Multiple possible variants found:

• chr5-115525024-C-A
• chr5-115525024-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020177.3(FEM1C):​c.1138G>T​(p.Ala380Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,400 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict 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. A380T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FEM1C NM_020177.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.06
• Publications: 0 publications found

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]

FEM1C Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Illumina

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21703348).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020177.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FEM1C	NM_020177.3	MANE Select	c.1138G>T	p.Ala380Ser	missense	Exon 3 of 3	NP_064562.1	Q96JP0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FEM1C	ENST00000274457.5	TSL:1 MANE Select	c.1138G>T	p.Ala380Ser	missense	Exon 3 of 3	ENSP00000274457.3	Q96JP0
	FEM1C	ENST00000855971.1		c.1138G>T	p.Ala380Ser	missense	Exon 3 of 3	ENSP00000526030.1
	FEM1C	ENST00000855972.1		c.1138G>T	p.Ala380Ser	missense	Exon 2 of 2	ENSP00000526031.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461400 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726988

African (AFR) AF: 0.00 AC: 0 AN: 33450

American (AMR) AF: 0.00 AC: 0 AN: 44644

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86220

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53382

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111776

Other (OTH) AF: 0.00 AC: 0 AN: 60376

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.064	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	21
DANN	Benign	0.89
DEOGEN2	Benign	0.032	T
Eigen	Benign	0.043
Eigen_PC	Benign	0.22
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.0077	T
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		4.1
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.10	N
REVEL	Benign	0.11
Sift	Benign	0.53	T
Sift4G	Benign	0.56	T
Polyphen		0.0050	B
Vest4		0.28
MutPred		0.38		Gain of disorder (P = 0.017)
MVP		0.43
MPC		0.53
ClinPred		0.55	D
GERP RS		5.5
Varity_R		0.23
gMVP		0.44
Mutation Taster		=77/23	polymorphism

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

Other links and lift over

dbSNP: rs748705585; hg19: chr5-114860721;