8-116648899-C-G

Variant names:

• chr8-116648899-C-G
• NM_003756.3:c.735G>C

Variant summary

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

The NM_003756.3(EIF3H):​c.735G>C​(p.Leu245Phe) 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. 14/22 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)
• Consequence: EIF3H NM_003756.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.03

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]

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=0.26350826).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF3H	NM_003756.3	c.735G>C	p.Leu245Phe	missense_variant	Exon 6 of 8	ENST00000521861.6	NP_003747.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EIF3H	ENST00000521861.6	c.735G>C	p.Leu245Phe	missense_variant	Exon 6 of 8	1	NM_003756.3	ENSP00000429931.1
EIF3H	ENST00000276682.8	c.777G>C	p.Leu259Phe	missense_variant	Exon 8 of 10	2		ENSP00000276682.4
EIF3H	ENST00000518949.5	c.639G>C	p.Leu213Phe	missense_variant	Exon 6 of 6	3		ENSP00000428195.1
EIF3H	ENST00000520289.1	n.739G>C		non_coding_transcript_exon_variant	Exon 3 of 4	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 10, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.735G>C (p.L245F) alteration is located in exon 6 (coding exon 6) of the EIF3H gene. This alteration results from a G to C substitution at nucleotide position 735, causing the leucine (L) at amino acid position 245 to be replaced by a phenylalanine (F). 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	0.17
BayesDel_addAF	Benign	-0.079	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T;.;T;T
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.26	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L;.;.;.
PhyloP100		1.0
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.1	N;.;N;N
REVEL	Benign	0.14
Sift	Benign	0.83	T;.;T;T
Sift4G	Benign	0.81	T;T;T;T
Polyphen		0.93	P;.;P;.
Vest4		0.50
MutPred		0.36		.;.;Loss of disorder (P = 0.0776);.;
MVP		0.63
MPC		0.34
ClinPred		0.92	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.075
gMVP		0.41
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

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Other links and lift over

hg19: chr8-117661138;