12-92787941-C-T

Variant names:

• chr12-92787941-C-T
• rs771186467
• NM_003566.4:c.3076G>A

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.3076G>A​(p.Glu1026Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,460,988 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. E1026Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: EEA1 NM_003566.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.63
• 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=0.21657261).

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.3076G>A	p.Glu1026Lys	missense	Exon 22 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.3076G>A	p.Glu1026Lys	missense	Exon 22 of 29	ENSP00000317955.8	Q15075
	EEA1	ENST00000962097.1		c.3292G>A	p.Glu1098Lys	missense	Exon 23 of 30	ENSP00000632156.1
	EEA1	ENST00000931425.1		c.2950G>A	p.Glu984Lys	missense	Exon 22 of 29	ENSP00000601484.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1460988 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726752

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33434

American (AMR) AF: 0.00 AC: 0 AN: 44640

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39614

South Asian (SAS) AF: 0.00 AC: 0 AN: 86150

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53336

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111624

Other (OTH) AF: 0.00 AC: 0 AN: 60328

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Uncertain	0.053	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T
Eigen	Benign	0.043
Eigen_PC	Benign	0.19
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		5.6
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.19
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.058	T
Polyphen		0.46	P
Vest4		0.37
MutPred		0.32		Gain of MoRF binding (P = 0.0049)
MVP		0.68
MPC		0.31
ClinPred		0.90	D
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.20
gMVP		0.27
Mutation Taster		=62/38	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: rs771186467; hg19: chr12-93181717; COSMIC: COSV107374542;