chr1-20829186-A-G

Position:

• chr1-20829186-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001391906.1(EIF4G3):​c.4148T>C​(p.Met1383Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00132 in 1,613,978 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0069 (10 hom., cov: 32)
  • Exomes 𝑓: 0.00075 (16 hom.)
• Consequence: EIF4G3 NM_001391906.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 8.84

Genes affected

EIF4G3 (HGNC:3298): (eukaryotic translation initiation factor 4 gamma 3) The protein encoded by this gene is thought to be part of the eIF4F protein complex, which is involved in mRNA cap recognition and transport of mRNAs to the ribosome. Interestingly, a microRNA (miR-520c-3p) has been found that negatively regulates synthesis of the encoded protein, and this leads to a global decrease in protein translation and cell proliferation. Therefore, this protein is a key component of the anti-tumor activity of miR-520c-3p. [provided by RefSeq, May 2016]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009413511).
• BP6: Variant 1-20829186-A-G is Benign according to our data. Variant chr1-20829186-A-G is described in ClinVar as [Benign]. Clinvar id is 786717.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00687 (1046/152288) while in subpopulation AFR AF= 0.0241 (1002/41556). AF 95% confidence interval is 0.0229. There are 10 homozygotes in gnomad4. There are 497 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 10 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EIF4G3	NM_001391906.1	c.4148T>C	p.Met1383Thr	missense_variant	31/37	ENST00000602326.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EIF4G3	ENST00000602326.6	c.4148T>C	p.Met1383Thr	missense_variant	31/37	1	NM_001391906.1	A2

Frequencies

GnomAD3 genomes AF: 0.00685 AC: 1043 AN: 152170 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.0241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00164 AC: 412 AN: 251140 Hom.: 7 AF XY: 0.00117 AC XY: 159 AN XY: 135720

Gnomad AFR exome AF: 0.0222

Gnomad AMR exome AF: 0.00113

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000529

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000747 AC: 1092 AN: 1461690 Hom.: 16 Cov.: 31 AF XY: 0.000659 AC XY: 479 AN XY: 727144

Gnomad4 AFR exome AF: 0.0257

Gnomad4 AMR exome AF: 0.00136

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000899

Gnomad4 OTH exome AF: 0.00224

GnomAD4 genome AF: 0.00687 AC: 1046 AN: 152288 Hom.: 10 Cov.: 32 AF XY: 0.00667 AC XY: 497 AN XY: 74470

Gnomad4 AFR AF: 0.0241

Gnomad4 AMR AF: 0.00235

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00126 Hom.: 0

Bravo AF: 0.00814

ESP6500AA AF: 0.0261 AC: 115

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00208 AC: 252

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 29, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	.;T;.;T;T
Eigen	Uncertain	0.62
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;D;D;D;D
MetaRNN	Benign	0.0094	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	.;L;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.6	D;D;.;.;.
REVEL	Uncertain	0.38
Sift	Uncertain	0.027	D;T;.;.;.
Sift4G	Benign	0.13	T;T;T;T;D
Polyphen		0.97	.;D;.;.;.
Vest4		0.66
MVP		0.18
MPC		0.90
ClinPred		0.038	T
GERP RS		5.7
Varity_R		0.52
gMVP		0.90

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

LitVar

Other links and lift over

dbSNP: rs111817671; hg19: chr1-21155679; COSMIC: COSV99059241;