Genetic Variant EIF4A1:p.Ser4Arg (chr17-7572853-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_001416.4(EIF4A1):c.12C>G(p.Ser4Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,802 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 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: 0.0000027 ( 0 hom. )

Consequence

EIF4A1
NM_001416.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.333

Variant links:

Genes affected

EIF4A1 (HGNC:3282): (eukaryotic translation initiation factor 4A1) Enables double-stranded RNA binding activity. Predicted to be involved in cytoplasmic translational initiation. Located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

EIF4A1 links:

SENP3-EIF4A1 (HGNC:49182): (SENP3-EIF4A1 readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring SUMO1/sentrin/SMT3 specific peptidase 3 (SENP3) and eukaryotic translation initiation factor 4A1 (EIF4A1) genes on chromosome 17. The read-through transcript is a candidate for nonsense-mediated mRNA decay (NMD), and is thus unlikely to produce a protein product. [provided by RefSeq, Mar 2011]

SENP3-EIF4A1 links:

ENSG00000264772 (HGNC:):

ENSG00000264772 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1

In a modified_residue Phosphoserine (size 0) in uniprot entity IF4A1_HUMAN

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.15153933).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF4A1	NM_001416.4 link	c.12C>G	p.Ser4Arg	missense_variant	Exon 1 of 11	ENST00000293831.13	NP_001407.1	P60842-1
EIF4A1	NM_001204510.2 link	c.12C>G	p.Ser4Arg	missense_variant	Exon 1 of 11		NP_001191439.1	P60842-2
SENP3-EIF4A1	NR_037926.1 link	n.2574C>G		non_coding_transcript_exon_variant	Exon 12 of 22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
EIF4A1	ENST00000293831.13 link	c.12C>G	p.Ser4Arg	missense_variant	Exon 1 of 11	1	NM_001416.4	ENSP00000293831.8	P60842-1
SENP3-EIF4A1	ENST00000614237.1 link	n.*458C>G		non_coding_transcript_exon_variant	Exon 11 of 21	2		ENSP00000483614.1	A0A087X0R7
SENP3-EIF4A1	ENST00000614237.1 link	n.*458C>G		3_prime_UTR_variant	Exon 11 of 21	2		ENSP00000483614.1	A0A087X0R7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461802

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727220

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 17, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.12C>G (p.S4R) alteration is located in exon 1 (coding exon 1) of the EIF4A1 gene. This alteration results from a C to G substitution at nucleotide position 12, causing the serine (S) at amino acid position 4 to be replaced by an arginine (R). 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

Uncertain

0.36

BayesDel_addAF

Benign

-0.043

BayesDel_noAF

Benign

-0.30

CADD

Benign

DANN

Benign

0.78

DEOGEN2

Benign

0.24

.;T;.;.;.;T

Eigen

Benign

-0.79

Eigen_PC

Benign

-0.62

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.87

D;D;D;D;D;D

M_CAP

Benign

0.014

MetaRNN

Benign

0.15

T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

.;L;.;L;.;.

PROVEAN

Benign

-0.66

.;N;.;.;.;.

REVEL

Benign

0.25

Sift

Uncertain

0.012

.;D;.;.;.;.

Sift4G

Benign

0.087

T;T;T;T;T;T

Polyphen

0.035

.;B;.;.;.;.

Vest4

0.53, 0.55, 0.54

MutPred

0.20

Gain of MoRF binding (P = 5e-04);Gain of MoRF binding (P = 5e-04);Gain of MoRF binding (P = 5e-04);Gain of MoRF binding (P = 5e-04);Gain of MoRF binding (P = 5e-04);Gain of MoRF binding (P = 5e-04);

MVP

0.72

MPC

.;5.81669046081E-4;.;.;.;.

ClinPred

0.16

GERP RS

1.4

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.7

Varity_R

0.11

gMVP

0.70

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over