14-103339203-C-G

Variant names:

• chr14-103339203-C-G
• rs2089324665
• NM_001969.5:c.776C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001969.5(EIF5):​c.776C>G​(p.Ser259Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000248 in 1,610,512 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: EIF5 NM_001969.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.98
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2839424).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001969.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF5	NM_001969.5	MANE Select	c.776C>G	p.Ser259Cys	missense	Exon 9 of 12	NP_001960.2
	EIF5	NM_183004.5		c.776C>G	p.Ser259Cys	missense	Exon 8 of 11	NP_892116.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF5	ENST00000216554.8	TSL:1 MANE Select	c.776C>G	p.Ser259Cys	missense	Exon 9 of 12	ENSP00000216554.3	P55010
	EIF5	ENST00000392715.6	TSL:1	c.776C>G	p.Ser259Cys	missense	Exon 8 of 11	ENSP00000376477.2	P55010
	EIF5	ENST00000558506.1	TSL:1	c.776C>G	p.Ser259Cys	missense	Exon 7 of 10	ENSP00000453743.1	P55010

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152196 Hom.: 0 Cov.: 33

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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1458316 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 725412

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33104

American (AMR) AF: 0.00 AC: 0 AN: 43660

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26040

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.00 AC: 0 AN: 85298

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111164

Other (OTH) AF: 0.00 AC: 0 AN: 60244

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000343967), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152196 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74350

African (AFR) AF: 0.0000241 AC: 1 AN: 41452

American (AMR) AF: 0.00 AC: 0 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.017	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	22
DANN	Benign	0.94
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.072
Eigen_PC	Benign	0.052
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	1.9	L
PhyloP100		6.0
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.28
Sift	Benign	0.085	T
Sift4G	Benign	0.15	T
Polyphen		0.35	B
Vest4		0.46
MutPred		0.39		Loss of disorder (P = 0.0087)
MVP		0.62
ClinPred		0.77	D
GERP RS		2.9
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.0
Varity_R		0.51
gMVP		0.25
Mutation Taster		=68/32	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

Other links and lift over

dbSNP: rs2089324665; hg19: chr14-103805540;