12-92780288-T-A

Variant names:

• chr12-92780288-T-A
• rs146201229
• NM_003566.4:c.3460A>T

Variant summary

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

The NM_003566.4(EEA1):​c.3460A>T​(p.Ser1154Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000692 in 1,444,538 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. S1154R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: EEA1 NM_003566.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.31
• Publications: 0 publications found

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]

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=0.217266).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003566.4. 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
	EEA1	NM_003566.4	MANE Select	c.3460A>T	p.Ser1154Cys	missense	Exon 24 of 29	NP_003557.3	Q15075

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EEA1	ENST00000322349.13	TSL:1 MANE Select	c.3460A>T	p.Ser1154Cys	missense	Exon 24 of 29	ENSP00000317955.8	Q15075
	EEA1	ENST00000962097.1		c.3676A>T	p.Ser1226Cys	missense	Exon 25 of 30	ENSP00000632156.1
	EEA1	ENST00000931425.1		c.3334A>T	p.Ser1112Cys	missense	Exon 24 of 29	ENSP00000601484.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.92e-7 AC: 1 AN: 1444538 Hom.: 0 Cov.: 30 AF XY: 0.00000139 AC XY: 1 AN XY: 718156

African (AFR) AF: 0.00 AC: 0 AN: 32064

American (AMR) AF: 0.00 AC: 0 AN: 39760

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25754

East Asian (EAS) AF: 0.00 AC: 0 AN: 39054

South Asian (SAS) AF: 0.0000122 AC: 1 AN: 81958

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53206

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5704

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1107332

Other (OTH) AF: 0.00 AC: 0 AN: 59706

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	-0.096	T
BayesDel_noAF	Benign	-0.38
CADD	Uncertain	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.23	T
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.2	L
PhyloP100		2.3
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.092
Sift	Benign	0.11	T
Sift4G	Benign	0.10	T
Polyphen		0.99	D
Vest4		0.26
MutPred		0.22		Loss of phosphorylation at S1154 (P = 0.0315)
MVP		0.49
MPC		0.18
ClinPred		0.86	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.083
gMVP		0.12
Mutation Taster		=89/11	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: rs146201229; hg19: chr12-93174064;