Genetic Variant EIF3H:p.Pro311Arg (chr8-116646500-G-C) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_003756.3(EIF3H):c.932C>G(p.Pro311Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P311L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

EIF3H
NM_003756.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 10.0

Variant links:

Genes affected

EIF3H (HGNC:3273): (eukaryotic translation initiation factor 3 subunit H) Enables deubiquitinase activity. Contributes to translation initiation factor activity. Involved in negative regulation of proteasomal ubiquitin-dependent protein catabolic process and translational initiation. Located in extracellular exosome and membrane. Part of eukaryotic translation initiation factor 3 complex. Implicated in breast cancer; prostate cancer; and prostate carcinoma. Biomarker of prostate cancer. [provided by Alliance of Genome Resources, Apr 2022]

EIF3H links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.842

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF3H	NM_003756.3 link	c.932C>G	p.Pro311Arg	missense_variant	Exon 7 of 8	ENST00000521861.6	NP_003747.1	O15372Q6IB98

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
EIF3H	ENST00000521861.6 link	c.932C>G	p.Pro311Arg	missense_variant	Exon 7 of 8	1	NM_003756.3	ENSP00000429931.1	O15372
EIF3H	ENST00000276682.8 link	c.974C>G	p.Pro325Arg	missense_variant	Exon 9 of 10	2		ENSP00000276682.4	B3KS98
EIF3H	ENST00000520289.1 link	n.*81C>G		downstream_gene_variant		2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461886

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1112004

Other (OTH)

AF:

0.00

AC:

AN:

60396

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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.14

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.67

D;.;T

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.95

D;D;D

M_CAP

Benign

0.064

MetaRNN

Pathogenic

0.84

D;D;D

MetaSVM

Uncertain

0.29

MutationAssessor

Pathogenic

3.3

M;.;.

PhyloP100

PrimateAI

Uncertain

0.73

PROVEAN

Pathogenic

-7.5

D;.;D

REVEL

Uncertain

0.54

Sift

Pathogenic

0.0

D;.;D

Sift4G

Uncertain

0.0020

D;D;D

Polyphen

1.0

D;.;D

Vest4

0.92

MutPred

0.48

.;.;Loss of glycosylation at P325 (P = 0.0127);

MVP

0.88

MPC

0.50

ClinPred

1.0

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.79

gMVP

0.77

Mutation Taster

=61/39

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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8-116646500-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

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