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chr19-4793477-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_018708.3(FEM1A):​c.1623G>A​(p.Met541Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000151 in 1,460,374 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

FEM1A
NM_018708.3 missense

Scores

2
6
11

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.82
Variant links:
Genes affected
FEM1A (HGNC:16934): (fem-1 homolog A) Enables EP4 subtype prostaglandin E2 receptor binding activity and ubiquitin ligase-substrate adaptor activity. Involved in negative regulation of inflammatory response and ubiquitin-dependent protein catabolic process via the C-end degron rule pathway. Part of Cul2-RING ubiquitin ligase complex. Is active in mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.41324896).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
FEM1ANM_018708.3 linkuse as main transcriptc.1623G>A p.Met541Ile missense_variant 1/1 ENST00000269856.5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
FEM1AENST00000269856.5 linkuse as main transcriptc.1623G>A p.Met541Ile missense_variant 1/1 NM_018708.3 P1
ENST00000601192.1 linkuse as main transcriptn.2079C>T non_coding_transcript_exon_variant 1/24

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000797
AC:
2
AN:
250930
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135674
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000177
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000151
AC:
22
AN:
1460374
Hom.:
0
Cov.:
31
AF XY:
0.0000151
AC XY:
11
AN XY:
726508
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000189
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.0000113
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsApr 25, 2022The c.1623G>A (p.M541I) alteration is located in exon 1 (coding exon 1) of the FEM1A gene. This alteration results from a G to A substitution at nucleotide position 1623, causing the methionine (M) at amino acid position 541 to be replaced by an isoleucine (I). 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
0.83
BayesDel_addAF
Uncertain
0.070
D
BayesDel_noAF
Benign
-0.12
CADD
Benign
23
DANN
Uncertain
0.99
DEOGEN2
Benign
0.018
T
Eigen
Benign
-0.12
Eigen_PC
Benign
0.14
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.80
T
M_CAP
Benign
0.026
D
MetaRNN
Benign
0.41
T
MetaSVM
Benign
-0.97
T
MutationAssessor
Benign
1.8
L
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.72
T
PROVEAN
Benign
-0.47
N
REVEL
Uncertain
0.29
Sift
Uncertain
0.019
D
Sift4G
Uncertain
0.030
D
Polyphen
0.014
B
Vest4
0.61
MutPred
0.54
Loss of ubiquitination at K545 (P = 0.0734);
MVP
0.14
ClinPred
0.67
D
GERP RS
5.0
Varity_R
0.49
gMVP
0.68

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs753896931; hg19: chr19-4793489; API