19-38632643-G-A

Variant names:

• chr19-38632643-G-A
• rs547512433
• NM_013234.4:c.464G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_013234.4(EIF3K):​c.464G>A​(p.Arg155His) variant causes a missense change. The variant allele was found at a frequency of 0.000131 in 1,613,606 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R155C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: EIF3K NM_013234.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.20

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]

ACMG classification

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=0.14098334).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF3K	NM_013234.4	c.464G>A	p.Arg155His	missense_variant	Exon 6 of 8	ENST00000248342.9	NP_037366.1
EIF3K	NM_001308393.2	c.203G>A	p.Arg68His	missense_variant	Exon 6 of 8		NP_001295322.1
EIF3K	NM_001300992.2	c.421+147G>A		intron_variant	Intron 5 of 6		NP_001287921.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EIF3K	ENST00000248342.9	c.464G>A	p.Arg155His	missense_variant	Exon 6 of 8	1	NM_013234.4	ENSP00000248342.3

Frequencies

GnomAD3 genomes AF: 0.0000855 AC: 13 AN: 152110 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000771

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.0000399 AC: 10 AN: 250720 Hom.: 1 AF XY: 0.0000221 AC XY: 3 AN XY: 135500

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000218

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000441

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000135 AC: 198 AN: 1461378 Hom.: 0 Cov.: 31 AF XY: 0.000121 AC XY: 88 AN XY: 726968

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00224

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000873

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152228 Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74426

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000772

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.0000565 Hom.: 0

Bravo AF: 0.0000680

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000165 AC: 2

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 28, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.464G>A (p.R155H) alteration is located in exon 6 (coding exon 6) of the EIF3K gene. This alteration results from a G to A substitution at nucleotide position 464, causing the arginine (R) at amino acid position 155 to be replaced by a histidine (H). 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	0.071
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.43
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T;.;T;.;.;.
Eigen	Benign	-0.021
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.88	D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.14	T;T;T;T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.4	.;.;L;.;L;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.9	.;.;N;N;N;.
REVEL	Benign	0.091
Sift	Benign	0.16	.;.;T;T;T;.
Sift4G	Benign	0.15	T;T;T;T;T;T
Polyphen		0.039, 0.0020	.;.;B;B;.;.
Vest4		0.38
MutPred		0.51		.;.;Gain of catalytic residue at L157 (P = 0.0934);.;Gain of catalytic residue at L157 (P = 0.0934);.;
MVP		0.74
MPC		0.47
ClinPred		0.091	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.33
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs547512433; hg19: chr19-39123283;