19-38624117-G-A

Variant names:

• chr19-38624117-G-A
• rs763050430
• NM_013234.4:c.199G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_013234.4(EIF3K):​c.199G>A​(p.Ala67Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000026 in 1,613,978 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 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: EIF3K NM_013234.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.66

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22242707).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF3K	NM_013234.4	c.199G>A	p.Ala67Thr	missense_variant	Exon 3 of 8	ENST00000248342.9	NP_037366.1
EIF3K	NM_001300992.2	c.199G>A	p.Ala67Thr	missense_variant	Exon 3 of 7		NP_001287921.1
EIF3K	NM_001308393.2	c.-63G>A		5_prime_UTR_variant	Exon 3 of 8		NP_001295322.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EIF3K	ENST00000248342.9	c.199G>A	p.Ala67Thr	missense_variant	Exon 3 of 8	1	NM_013234.4	ENSP00000248342.3

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152114 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000239 AC: 6 AN: 251468 AF XY: 0.0000441

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000274 AC: 40 AN: 1461864 Hom.: 0 Cov.: 31 AF XY: 0.0000358 AC XY: 26 AN XY: 727228

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 33480

Gnomad4 AMR exome AF: 0.0000447 AC: 2 AN: 44720

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26134

Gnomad4 EAS exome AF: 0.000176 AC: 7 AN: 39698

Gnomad4 SAS exome AF: 0.000139 AC: 12 AN: 86258

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53418

Gnomad4 NFE exome AF: 0.0000171 AC: 19 AN: 1111992

Gnomad4 Remaining exome AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152114 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74316

Gnomad4 AFR AF: 0.0000241 AC: 0.0000241394 AN: 0.0000241394

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.000207 AC: 0.000207383 AN: 0.000207383

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.00 AC: 0 AN: 0

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 06, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.199G>A (p.A67T) alteration is located in exon 3 (coding exon 3) of the EIF3K gene. This alteration results from a G to A substitution at nucleotide position 199, causing the alanine (A) at amino acid position 67 to be replaced by a threonine (T). 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	0.22
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.019	T;T;.;.;.;T
Eigen	Benign	0.030
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.92	D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.22	T;T;T;T;T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.4	.;L;.;L;.;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.4	.;N;.;N;.;.
REVEL	Benign	0.14
Sift	Benign	0.70	.;T;.;T;.;.
Sift4G	Benign	0.34	T;T;T;T;T;T
Polyphen		0.12	.;B;.;.;.;.
Vest4		0.64
MutPred		0.50		.;Gain of ubiquitination at K72 (P = 0.1062);Gain of ubiquitination at K72 (P = 0.1062);Gain of ubiquitination at K72 (P = 0.1062);.;Gain of ubiquitination at K72 (P = 0.1062);
MVP		0.52
MPC		0.39
ClinPred		0.25	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.29
gMVP		0.31
Mutation Taster		=57/43	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs763050430; hg19: chr19-39114757;