Genetic Variant EIF3CL:p.Lys321Arg (chr16-28391833-T-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.962A>G(p.Lys321Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000519 in 1,320,584 control chromosomes in the GnomAD database, including 162 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00049 ( 9 hom., cov: 15)

Exomes 𝑓: 0.00052 ( 162 hom. )

Failed GnomAD Quality Control

Consequence

EIF3CL
NM_001317857.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.96

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=0.09324938).

BS2

High Homozygotes in GnomAdExome4 at 162 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF3CL	NM_001317857.2 link	c.962A>G	p.Lys321Arg	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.962A>G	p.Lys321Arg	missense_variant	Exon 10 of 21	1	NM_001317857.2	ENSP00000370258.5		B5ME19
EIF3CL	ENST00000398944.7 link	c.962A>G	p.Lys321Arg	missense_variant	Exon 10 of 21	5		ENSP00000381917.3		B5ME19

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

117062

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.0000845

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000880

Gnomad FIN

AF:

0.000807

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000873

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000665

AC:

149

AN:

223944

Hom.:

AF XY:

0.000660

AC XY:

AN XY:

121162

show subpopulations

Gnomad AFR exome

AF:

0.000125

Gnomad AMR exome

AF:

0.000126

Gnomad ASJ exome

AF:

0.000473

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000141

Gnomad FIN exome

AF:

0.000598

Gnomad NFE exome

AF:

0.00114

Gnomad OTH exome

AF:

0.00145

GnomAD4 exome

AF:

0.000519

AC:

686

AN:

1320584

Hom.:

162

Cov.:

AF XY:

0.000496

AC XY:

326

AN XY:

657178

show subpopulations

Gnomad4 AFR exome

AF:

0.0000918

Gnomad4 AMR exome

AF:

0.000171

Gnomad4 ASJ exome

AF:

0.000232

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000239

Gnomad4 FIN exome

AF:

0.000567

Gnomad4 NFE exome

AF:

0.000588

Gnomad4 OTH exome

AF:

0.000536

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000495

AC:

AN:

117186

Hom.:

Cov.:

AF XY:

0.000499

AC XY:

AN XY:

56144

show subpopulations

Gnomad4 AFR

AF:

0.0000842

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000883

Gnomad4 FIN

AF:

0.000807

Gnomad4 NFE

AF:

0.000873

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000192

Hom.:

ESP6500AA

AF:

0.000232

AC:

ESP6500EA

AF:

0.000497

AC:

ExAC

AF:

0.000789

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 11, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.962A>G (p.K321R) alteration is located in exon 10 (coding exon 9) of the EIF3CL gene. This alteration results from a A to G substitution at nucleotide position 962, causing the lysine (K) at amino acid position 321 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

Benign

0.26

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.30

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.056

T;T

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.92

D;.

M_CAP

Benign

0.037

MetaRNN

Benign

0.093

T;T

MetaSVM

Uncertain

-0.26

MutationAssessor

Uncertain

2.5

M;M

PrimateAI

Pathogenic

0.83

PROVEAN

Uncertain

-2.7

D;D

REVEL

Benign

0.18

Sift

Uncertain

0.017

D;D

Sift4G

Uncertain

0.019

D;D

Polyphen

0.94

P;P

Vest4

0.46

MVP

0.095

ClinPred

0.24

GERP RS

3.8

Varity_R

0.51

gMVP

0.13

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.13

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