Genetic Variant NM_001969.5:c.521C>T (chr14-103338408-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_001969.5(EIF5):c.521C>T(p.Ser174Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000249 in 1,606,900 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

EIF5
NM_001969.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.00

Publications

0 publications found

Variant links:

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]

EIF5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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.521C>T	p.Ser174Phe	missense	Exon 7 of 12	NP_001960.2
	EIF5	NM_183004.5		c.521C>T	p.Ser174Phe	missense	Exon 6 of 11	NP_892116.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EIF5	ENST00000216554.8	TSL:1 MANE Select	c.521C>T	p.Ser174Phe	missense	Exon 7 of 12	ENSP00000216554.3	P55010
EIF5	ENST00000392715.6	TSL:1	c.521C>T	p.Ser174Phe	missense	Exon 6 of 11	ENSP00000376477.2	P55010
EIF5	ENST00000558506.1	TSL:1	c.521C>T	p.Ser174Phe	missense	Exon 5 of 10	ENSP00000453743.1	P55010

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152058

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000433

AC:

AN:

231196

AF XY:

0.00000796

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000996

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1454842

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

723404

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33094

American (AMR)

AF:

0.00

AC:

AN:

43720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26044

East Asian (EAS)

AF:

0.00

AC:

AN:

39182

South Asian (SAS)

AF:

0.00

AC:

AN:

85596

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53138

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1108214

Other (OTH)

AF:

0.00

AC:

AN:

60096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152058

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74300

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

41376

American (AMR)

AF:

0.0000655

AC:

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5204

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68004

Other (OTH)

AF:

0.00

AC:

AN:

2084

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Uncertain

0.089

BayesDel_noAF

Benign

-0.11

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.26

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.89

M_CAP

Uncertain

0.13

MetaRNN

Uncertain

0.62

MetaSVM

Uncertain

0.041

MutationAssessor

Uncertain

2.0

PhyloP100

4.0

PrimateAI

Uncertain

0.77

PROVEAN

Uncertain

-2.9

REVEL

Uncertain

0.46

Sift

Uncertain

0.0080

Sift4G

Uncertain

0.016

Polyphen

0.90

Vest4

0.48

MVP

0.69

ClinPred

0.75

GERP RS

5.0

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.6

Varity_R

0.30

gMVP

0.27

Mutation Taster

=65/35

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over