Genetic Variant NM_013234.4:c.491A>T (chr19-38632670-A-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_013234.4(EIF3K):c.491A>T(p.Asp164Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000329 in 1,612,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

EIF3K
NM_013234.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.86

Variant links:

Genes affected

EIF3K (HGNC:24656): (eukaryotic translation initiation factor 3 subunit K) The 700-kD eukaryotic translation initiation factor-3 (eIF3) is the largest eIF and contains at least 12 subunits, including EIF2S12. eIF3 plays an essential role in translation by binding directly to the 40S ribosomal subunit and promoting formation of the 40S preinitiation complex (Mayeur et al., 2003 [PubMed 14519125]).[supplied by OMIM, Mar 2008]

EIF3K links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.249105).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF3K	NM_013234.4 link	c.491A>T	p.Asp164Val	missense_variant	Exon 6 of 8	ENST00000248342.9	NP_037366.1	Q9UBQ5-1
EIF3K	NM_001308393.2 link	c.230A>T	p.Asp77Val	missense_variant	Exon 6 of 8		NP_001295322.1	K7EK53
EIF3K	NM_001300992.2 link	c.421+174A>T		intron_variant	Intron 5 of 6		NP_001287921.1	K7ERF1U3LUI4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EIF3K	ENST00000248342.9 link	c.491A>T	p.Asp164Val	missense_variant	Exon 6 of 8	1	NM_013234.4	ENSP00000248342.3		Q9UBQ5-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152118

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:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000882

AC:

AN:

249368

Hom.:

AF XY:

0.0000816

AC XY:

AN XY:

134764

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000608

Gnomad NFE exome

AF:

0.0000444

Gnomad OTH exome

AF:

0.000657

GnomAD4 exome

AF:

0.0000335

AC:

AN:

1460762

Hom.:

Cov.:

AF XY:

0.0000330

AC XY:

AN XY:

726614

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:

0.000750

Gnomad4 NFE exome

AF:

0.00000540

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152118

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74294

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:

0.000283

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.0000906

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 21, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.491A>T (p.D164V) alteration is located in exon 6 (coding exon 6) of the EIF3K gene. This alteration results from a A to T substitution at nucleotide position 491, causing the aspartic acid (D) at amino acid position 164 to be replaced by a valine (V). 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

Pathogenic

0.22

BayesDel_noAF

Pathogenic

0.19

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.078

T;.;T;.;.;.

Eigen

Uncertain

0.21

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Uncertain

0.94

M_CAP

Benign

0.032

MetaRNN

Benign

0.25

T;T;T;T;T;T

MetaSVM

Benign

-0.51

MutationAssessor

Benign

1.3

.;.;L;.;L;.

PrimateAI

Uncertain

0.58

PROVEAN

Uncertain

-3.2

.;.;D;D;D;.

REVEL

Uncertain

0.58

Sift

Benign

0.52

.;.;T;T;T;.

Sift4G

Benign

0.51

T;T;T;T;T;T

Polyphen

0.092, 0.44

.;.;B;B;.;.

Vest4

0.80

MutPred

0.37

.;.;Gain of catalytic residue at D164 (P = 0.0029);.;Gain of catalytic residue at D164 (P = 0.0029);.;

MVP

0.78

MPC

0.65

ClinPred

0.13

GERP RS

5.4

Varity_R

0.57

gMVP

0.72

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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