Genetic Variant EIF3CL:p.Ile331Ser (chr16-28391803-A-C) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001317857.2(EIF3CL):c.992T>G(p.Ile331Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000449 in 1,293,966 control chromosomes in the GnomAD database, including 123 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00024 ( 2 hom., cov: 14)

Exomes 𝑓: 0.00045 ( 123 hom. )

Failed GnomAD Quality Control

Consequence

EIF3CL
NM_001317857.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.09

Variant links:

Genes affected

EIF3CL (HGNC:26347): (eukaryotic translation initiation factor 3 subunit C like) The protein encoded by this gene is a core subunit of the eukaryotic translation initiation factor 3 (eIF3) complex. The encoded protein is nearly identical to another protein, eIF3c, from a related gene. The eIF3 complex binds the 40S ribosome and mRNAs to enable translation initiation. Several transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Dec 2015]

EIF3CL links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.08456606).

BS2

High Homozygotes in GnomAdExome4 at 123 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF3CL	NM_001317857.2 link	c.992T>G	p.Ile331Ser	missense_variant	Exon 10 of 21	ENST00000380876.5	NP_001304786.1	B5ME19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EIF3CL	ENST00000380876.5 link	c.992T>G	p.Ile331Ser	missense_variant	Exon 10 of 21	1	NM_001317857.2	ENSP00000370258.5		B5ME19
EIF3CL	ENST00000398944.7 link	c.992T>G	p.Ile331Ser	missense_variant	Exon 10 of 21	5		ENSP00000381917.3		B5ME19

Frequencies

GnomAD3 genomes

AF:

0.000237

AC:

AN:

105378

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000526

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000403

AC:

AN:

220998

Hom.:

AF XY:

0.000401

AC XY:

AN XY:

119660

show subpopulations

Gnomad AFR exome

AF:

0.0000631

Gnomad AMR exome

AF:

0.000129

Gnomad ASJ exome

AF:

0.00229

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000654

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000449

AC:

581

AN:

1293966

Hom.:

123

Cov.:

AF XY:

0.000451

AC XY:

291

AN XY:

645472

show subpopulations

Gnomad4 AFR exome

AF:

0.0000927

Gnomad4 AMR exome

AF:

0.000123

Gnomad4 ASJ exome

AF:

0.00146

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000535

Gnomad4 OTH exome

AF:

0.000264

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000237

AC:

AN:

105378

Hom.:

Cov.:

AF XY:

0.000239

AC XY:

AN XY:

50206

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000526

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000169

Hom.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00121

AC:

ExAC

AF:

0.000343

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 23, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.992T>G (p.I331S) alteration is located in exon 10 (coding exon 9) of the EIF3CL gene. This alteration results from a T to G substitution at nucleotide position 992, causing the isoleucine (I) at amino acid position 331 to be replaced by a serine (S). 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

Pathogenic

0.58

BayesDel_addAF

Benign

-0.088

BayesDel_noAF

Benign

-0.13

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.14

T;T

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.081

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.96

D;.

M_CAP

Benign

0.031

MetaRNN

Benign

0.085

T;T

MetaSVM

Benign

-0.88

MutationAssessor

Benign

1.5

L;L

PrimateAI

Uncertain

0.74

PROVEAN

Uncertain

-4.0

D;D

REVEL

Benign

0.25

Sift

Uncertain

0.0030

D;D

Sift4G

Uncertain

0.014

D;D

Polyphen

0.020

B;B

Vest4

0.67

MVP

0.22

ClinPred

0.19

GERP RS

3.8

Varity_R

0.69

gMVP

0.37

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over