19-4792131-G-A

Position:

• chr19-4792131-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_018708.3(FEM1A):​c.277G>A​(p.Ala93Thr) 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 (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FEM1A NM_018708.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.72

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]

ENSG00000269604 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FEM1A	NM_018708.3	c.277G>A	p.Ala93Thr	missense_variant	1/1	ENST00000269856.5	NP_061178.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FEM1A	ENST00000269856.5	c.277G>A	p.Ala93Thr	missense_variant	1/1	6	NM_018708.3	ENSP00000269856.3
ENSG00000269604	ENST00000601192.1	n.3300-118C>T		intron_variant		4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1367582 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 673514

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Dec 16, 2022

The c.277G>A (p.A93T) 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 277, causing the alanine (A) at amino acid position 93 to be replaced by a threonine (T). 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	0.72
BayesDel_addAF	Uncertain	0.039	T
BayesDel_noAF	Benign	-0.18
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.086	T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.20	D
MetaRNN	Uncertain	0.59	D
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	0.60	N
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.40
Sift	Benign	0.037	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.56
MutPred		0.24		Gain of MoRF binding (P = 0.1095);
MVP		0.26
ClinPred		0.99	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.41
gMVP		0.46

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: chr19-4792143;