chr12-92798903-C-A

Variant names:

• chr12-92798903-C-A
• NM_003566.4:c.2956G>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.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. 17/22 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.70
• 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=0.089134276).

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.2956G>T	p.Val986Phe	missense	Exon 21 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.2956G>T	p.Val986Phe	missense	Exon 21 of 29	ENSP00000317955.8	Q15075
	EEA1	ENST00000962097.1		c.3172G>T	p.Val1058Phe	missense	Exon 22 of 30	ENSP00000632156.1
	EEA1	ENST00000931425.1		c.2830G>T	p.Val944Phe	missense	Exon 21 of 29	ENSP00000601484.1

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

African (AFR) AF: 0.00 AC: 0 AN: 31662

American (AMR) AF: 0.00 AC: 0 AN: 37664

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24986

East Asian (EAS) AF: 0.00 AC: 0 AN: 39176

South Asian (SAS) AF: 0.00 AC: 0 AN: 79988

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51852

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5622

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1103858

Other (OTH) AF: 0.00 AC: 0 AN: 59180

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		-1.7
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
Mutation Taster		=89/11	polymorphism

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

Other links and lift over

hg19: chr12-93192679;