rs373405068

Variant names:

• chr12-92780347-C-A
• rs373405068
• NM_003566.4:c.3401G>T

Your query was ambiguous. Multiple possible variants found:

• chr12-92780347-C-A
• chr12-92780347-C-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.3401G>T​(p.Cys1134Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,448,524 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 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. C1134Y) 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: 0.415
• 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=0.103741646).

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.3401G>T	p.Cys1134Phe	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.3401G>T	p.Cys1134Phe	missense	Exon 24 of 29	ENSP00000317955.8	Q15075
	EEA1	ENST00000962097.1		c.3617G>T	p.Cys1206Phe	missense	Exon 25 of 30	ENSP00000632156.1
	EEA1	ENST00000931425.1		c.3275G>T	p.Cys1092Phe	missense	Exon 24 of 29	ENSP00000601484.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1448524 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 720764

African (AFR) AF: 0.00 AC: 0 AN: 32650

American (AMR) AF: 0.00 AC: 0 AN: 42770

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25884

East Asian (EAS) AF: 0.00 AC: 0 AN: 38996

South Asian (SAS) AF: 0.00 AC: 0 AN: 84048

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53222

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5712

European-Non Finnish (NFE) AF: 9.05e-7 AC: 1 AN: 1105386

Other (OTH) AF: 0.00 AC: 0 AN: 59856

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	21
DANN	Benign	0.95
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.41
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.063
Sift	Benign	0.080	T
Sift4G	Uncertain	0.047	D
Polyphen		0.23	B
Vest4		0.42
MutPred		0.12		Gain of ubiquitination at K1133 (P = 0.0846)
MVP		0.18
MPC		0.31
ClinPred		0.66	D
GERP RS		4.9
Varity_R		0.14
gMVP		0.089
Mutation Taster		=92/8	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: rs373405068; hg19: chr12-93174123;