14-103338455-C-A

Variant names:

• chr14-103338455-C-A
• rs61730315
• NM_001969.5:c.568C>A

Variant summary

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

The NM_001969.5(EIF5):​c.568C>A​(p.Pro190Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: EIF5 NM_001969.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.91

Genes affected

EIF5 (HGNC:3299): (eukaryotic translation initiation factor 5) Eukaryotic translation initiation factor-5 (EIF5) interacts with the 40S initiation complex to promote hydrolysis of bound GTP with concomitant joining of the 60S ribosomal subunit to the 40S initiation complex. The resulting functional 80S ribosomal initiation complex is then active in peptidyl transfer and chain elongations (summary by Si et al., 1996 [PubMed 8663286]).[supplied by OMIM, May 2010]

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=0.1918998).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF5	NM_001969.5	c.568C>A	p.Pro190Thr	missense_variant	Exon 7 of 12	ENST00000216554.8	NP_001960.2
EIF5	NM_183004.5	c.568C>A	p.Pro190Thr	missense_variant	Exon 6 of 11		NP_892116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EIF5	ENST00000216554.8	c.568C>A	p.Pro190Thr	missense_variant	Exon 7 of 12	1	NM_001969.5	ENSP00000216554.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 7.03e-7 AC: 1 AN: 1422798 Hom.: 0 Cov.: 32 AF XY: 0.00000142 AC XY: 1 AN XY: 704896

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: 0.00

Gnomad4 NFE exome AF: 9.16e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 01, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.568C>A (p.P190T) alteration is located in exon 7 (coding exon 5) of the EIF5 gene. This alteration results from a C to A substitution at nucleotide position 568, causing the proline (P) at amino acid position 190 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	0.078
BayesDel_addAF	Benign	0.0054	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.045	T;.;T;T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.81	.;T;.;T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.19	T;T;T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Uncertain	2.2	M;.;M;M
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	0.39	N;N;N;N
REVEL	Benign	0.26
Sift	Benign	0.47	T;D;T;T
Sift4G	Benign	0.58	T;T;T;T
Polyphen		0.26	B;.;B;B
Vest4		0.37
MutPred		0.25		Gain of phosphorylation at P190 (P = 0.0023);Gain of phosphorylation at P190 (P = 0.0023);Gain of phosphorylation at P190 (P = 0.0023);Gain of phosphorylation at P190 (P = 0.0023);
MVP		0.52
ClinPred		0.43	T
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.14
gMVP		0.19

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: rs61730315; hg19: chr14-103804792;