12-92798938-T-G

Position:

• chr12-92798938-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003566.4(EEA1):​c.2921A>C​(p.Gln974Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: EEA1 NM_003566.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.60

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

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=0.2634982).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EEA1	NM_003566.4	c.2921A>C	p.Gln974Pro	missense_variant	21/29	ENST00000322349.13	NP_003557.3
EEA1	XM_011538814.3	c.3047A>C	p.Gln1016Pro	missense_variant	22/30		XP_011537116.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EEA1	ENST00000322349.13	c.2921A>C	p.Gln974Pro	missense_variant	21/29	1	NM_003566.4	ENSP00000317955.8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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

Jun 10, 2022

The c.2921A>C (p.Q974P) alteration is located in exon 21 (coding exon 21) of the EEA1 gene. This alteration results from a A to C substitution at nucleotide position 2921, causing the glutamine (Q) at amino acid position 974 to be replaced by a proline (P). 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	0.31
BayesDel_addAF	Uncertain	0.028	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.40	T
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.058	D
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Uncertain	2.2	M
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-2.5	N
REVEL	Benign	0.19
Sift	Uncertain	0.012	D
Sift4G	Benign	0.096	T
Polyphen		0.80	P
Vest4		0.36
MutPred		0.19		Gain of helix (P = 0.0496);
MVP		0.53
MPC		0.37
ClinPred		0.76	D
GERP RS		5.5
Varity_R		0.59
gMVP		0.64

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: chr12-93192714;