12-92798903-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_003566.4(EEA1):​c.2956G>T​(p.Val986Phe) 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. 16/21 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)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

EEA1
NM_003566.4 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.70
Variant links:
Genes affected
EEA1 (HGNC:3185): (early endosome antigen 1) Enables 1-phosphatidylinositol binding activity; GTP-dependent protein binding activity; and protein homodimerization activity. Involved in endocytosis; vesicle fusion; and viral RNA genome replication. Located in cytosol and early endosome. Is extrinsic component of plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.089134276).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
EEA1NM_003566.4 linkc.2956G>T p.Val986Phe missense_variant Exon 21 of 29 ENST00000322349.13 NP_003557.3 Q15075
EEA1XM_011538814.3 linkc.3082G>T p.Val1028Phe missense_variant Exon 22 of 30 XP_011537116.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
EEA1ENST00000322349.13 linkc.2956G>T p.Val986Phe missense_variant Exon 21 of 29 1 NM_003566.4 ENSP00000317955.8 Q15075

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1433988
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
712576
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.:
32

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Mar 07, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.2956G>T (p.V986F) alteration is located in exon 21 (coding exon 21) of the EEA1 gene. This alteration results from a G to T substitution at nucleotide position 2956, causing the valine (V) at amino acid position 986 to be replaced by a phenylalanine (F). 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
0.086
BayesDel_addAF
Benign
-0.20
T
BayesDel_noAF
Benign
-0.52
CADD
Benign
0.040
DANN
Benign
0.96
DEOGEN2
Benign
0.17
T
Eigen
Benign
-1.3
Eigen_PC
Benign
-1.5
FATHMM_MKL
Benign
0.022
N
LIST_S2
Benign
0.69
T
M_CAP
Benign
0.048
D
MetaRNN
Benign
0.089
T
MetaSVM
Benign
-0.95
T
MutationAssessor
Benign
1.4
L
PrimateAI
Benign
0.30
T
PROVEAN
Benign
-0.71
N
REVEL
Benign
0.099
Sift
Benign
0.17
T
Sift4G
Benign
0.22
T
Polyphen
0.28
B
Vest4
0.27
MutPred
0.18
Loss of MoRF binding (P = 0.0975);
MVP
0.40
MPC
0.25
ClinPred
0.25
T
GERP RS
-11
Varity_R
0.078
gMVP
0.19

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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: chr12-93192679; API