rs118081497

Variant names:

• chr12-92782070-A-T
• rs118081497
• NM_003566.4:c.3216T>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003566.4(EEA1):​c.3216T>A​(p.Asn1072Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00261 in 1,612,704 control chromosomes in the GnomAD database, including 114 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0036 (11 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (103 hom.)
• Consequence: EEA1 NM_003566.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.438
• Publications: 7 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002201885).
• BP6: Variant 12-92782070-A-T is Benign according to our data. Variant chr12-92782070-A-T is described in ClinVar as Benign. ClinVar VariationId is 402817.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.058 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EEA1	NM_003566.4	MANE Select	c.3216T>A	p.Asn1072Lys	missense	Exon 23 of 29	NP_003557.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EEA1	ENST00000322349.13	TSL:1 MANE Select	c.3216T>A	p.Asn1072Lys	missense	Exon 23 of 29	ENSP00000317955.8

Frequencies

GnomAD3 genomes AF: 0.00363 AC: 552 AN: 152132 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.000869

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0240

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0229

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00719

GnomAD2 exomes AF: 0.0110 AC: 2768 AN: 250662 AF XY: 0.00839

Gnomad AFR exome AF: 0.000985

Gnomad AMR exome AF: 0.0656

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.0233

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000971

Gnomad OTH exome AF: 0.00688

GnomAD4 exome AF: 0.00251 AC: 3667 AN: 1460456 Hom.: 103 Cov.: 30 AF XY: 0.00215 AC XY: 1562 AN XY: 726544

African (AFR) AF: 0.000448 AC: 15 AN: 33452

American (AMR) AF: 0.0599 AC: 2671 AN: 44590

Ashkenazi Jewish (ASJ) AF: 0.000153 AC: 4 AN: 26098

East Asian (EAS) AF: 0.0176 AC: 696 AN: 39628

South Asian (SAS) AF: 0.000383 AC: 33 AN: 86132

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53336

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.0000477 AC: 53 AN: 1111176

Other (OTH) AF: 0.00320 AC: 193 AN: 60294

GnomAD4 genome AF: 0.00361 AC: 550 AN: 152248 Hom.: 11 Cov.: 32 AF XY: 0.00380 AC XY: 283 AN XY: 74426

African (AFR) AF: 0.000866 AC: 36 AN: 41552

American (AMR) AF: 0.0239 AC: 365 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0227 AC: 118 AN: 5192

South Asian (SAS) AF: 0.000830 AC: 4 AN: 4822

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68000

Other (OTH) AF: 0.00712 AC: 15 AN: 2108

Alfa AF: 0.00125 Hom.: 2

Bravo AF: 0.00682

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00900 AC: 1092

Asia WGS AF: 0.0150 AC: 51 AN: 3478

EpiCase AF: 0.0000548

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	17
DANN	Benign	0.89
DEOGEN2	Benign	0.084	T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.63
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.74	T
MetaRNN	Benign	0.0022	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		0.44
PrimateAI	Benign	0.44	T
PROVEAN	Benign	0.16	N
REVEL	Benign	0.044
Sift	Benign	0.48	T
Sift4G	Benign	0.89	T
Polyphen		0.19	B
Vest4		0.25
MutPred		0.23		Gain of ubiquitination at N1072 (P = 0.0198)
MPC		0.22
ClinPred		0.011	T
GERP RS		2.4
Varity_R		0.024
gMVP		0.12
Mutation Taster		=93/7	polymorphism (auto)

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: rs118081497; hg19: chr12-93175846;