NM_003754.3:c.227C>G

Variant names:

• chr11-7987579-C-G
• rs200904167
• NM_003754.3:c.227C>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_003754.3(EIF3F):​c.227C>G​(p.Ala76Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00278 in 1,597,176 control chromosomes in the GnomAD database, including 120 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A76C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.015 (55 hom., cov: 33)
  • Exomes 𝑓: 0.0015 (65 hom.)
• Consequence: EIF3F NM_003754.3 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.53
• Publications: 3 publications found

Genes affected

EIF3F (HGNC:3275): (eukaryotic translation initiation factor 3 subunit F) Enables deubiquitinase activity and identical protein binding activity. Contributes to translation initiation factor activity. Involved in IRES-dependent viral translational initiation; protein deubiquitination; and translational initiation. Located in membrane. Part of eukaryotic translation initiation factor 3 complex. Implicated in autosomal recessive non-syndromic intellectual disability. [provided by Alliance of Genome Resources, Apr 2022]

EIF3F Gene-Disease associations (from GenCC):

• syndromic intellectual disability

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• intellectual developmental disorder, autosomal recessive 67

  Inheritance: AR, Unknown Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002087891).
• BP6: Variant 11-7987579-C-G is Benign according to our data. Variant chr11-7987579-C-G is described in ClinVar as Benign. ClinVar VariationId is 3038067.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.05 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003754.3. 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
	EIF3F	NM_003754.3	MANE Select	c.227C>G	p.Ala76Gly	missense	Exon 1 of 8	NP_003745.1	O00303

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF3F	ENST00000651655.1	MANE Select	c.227C>G	p.Ala76Gly	missense	Exon 1 of 8	ENSP00000499218.1	O00303
	EIF3F	ENST00000531572.2	TSL:2	c.227C>G	p.Ala76Gly	missense	Exon 1 of 7	ENSP00000434286.2	H0YDT6
	EIF3F	ENST00000533626.5	TSL:2	c.227C>G	p.Ala76Gly	missense	Exon 3 of 10	ENSP00000431800.1	O00303

Frequencies

GnomAD3 genomes AF: 0.0149 AC: 2274 AN: 152246 Hom.: 54 Cov.: 33

Gnomad AFR AF: 0.0520

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00575

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00860

GnomAD2 exomes AF: 0.00351 AC: 791 AN: 225590 AF XY: 0.00277

Gnomad AFR exome AF: 0.0555

Gnomad AMR exome AF: 0.00181

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000695

Gnomad OTH exome AF: 0.00148

GnomAD4 exome AF: 0.00150 AC: 2163 AN: 1444812 Hom.: 65 Cov.: 31 AF XY: 0.00133 AC XY: 955 AN XY: 717454

African (AFR) AF: 0.0537 AC: 1748 AN: 32556

American (AMR) AF: 0.00206 AC: 88 AN: 42708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25214

East Asian (EAS) AF: 0.00 AC: 0 AN: 39158

South Asian (SAS) AF: 0.0000594 AC: 5 AN: 84192

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52548

Middle Eastern (MID) AF: 0.00143 AC: 6 AN: 4196

European-Non Finnish (NFE) AF: 0.0000851 AC: 94 AN: 1104944

Other (OTH) AF: 0.00374 AC: 222 AN: 59296

GnomAD4 genome AF: 0.0149 AC: 2273 AN: 152364 Hom.: 55 Cov.: 33 AF XY: 0.0140 AC XY: 1043 AN XY: 74508

African (AFR) AF: 0.0519 AC: 2156 AN: 41576

American (AMR) AF: 0.00575 AC: 88 AN: 15312

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68032

Other (OTH) AF: 0.00851 AC: 18 AN: 2116

Alfa AF: 0.00407 Hom.: 3

Bravo AF: 0.0173

ESP6500AA AF: 0.0419 AC: 166

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00432 AC: 519

ClinVar

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	EIF3F-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.010	T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.091	N
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N
PhyloP100		1.5
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.31	N
REVEL	Benign	0.076
Sift	Uncertain	0.011	D
Sift4G	Benign	0.065	T
Polyphen		0.0020	B
Vest4		0.13
MVP		0.18
MPC		0.28
ClinPred		0.020	T
GERP RS		3.2
PromoterAI		0.024	Neutral
Varity_R		0.13
gMVP		0.17
Mutation Taster		=97/3	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: rs200904167; hg19: chr11-8009126;