17-80146872-G-A

Position:

• chr17-80146872-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_014740.4(EIF4A3):​c.90C>T​(p.Thr30Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00229 in 1,611,532 control chromosomes in the GnomAD database, including 72 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (38 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (34 hom.)
• Consequence: EIF4A3 NM_014740.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.296

Genes affected

EIF4A3 (HGNC:18683): (eukaryotic translation initiation factor 4A3) This gene encodes a member of the DEAD box protein family. DEAD box proteins, characterized by the conserved motif Asp-Glu-Ala-Asp (DEAD), are putative RNA helicases. They are implicated in a number of cellular processes involving alteration of RNA secondary structure, such as translation initiation, nuclear and mitochondrial splicing, and ribosome and spliceosome assembly. Based on their distribution patterns, some members of this family are believed to be involved in embryogenesis, spermatogenesis, and cellular growth and division. The protein encoded by this gene is a nuclear matrix protein. Its amino acid sequence is highly similar to the amino acid sequences of the translation initiation factors eIF4AI and eIF4AII, two other members of the DEAD box protein family. [provided by RefSeq, Jul 2008]

EIF4A3 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 17-80146872-G-A is Benign according to our data. Variant chr17-80146872-G-A is described in ClinVar as [Benign]. Clinvar id is 787998.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.296 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0126 (1916/152322) while in subpopulation AFR AF= 0.0438 (1819/41564). AF 95% confidence interval is 0.0421. There are 38 homozygotes in gnomad4. There are 911 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 38 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EIF4A3	NM_014740.4	c.90C>T	p.Thr30Thr	synonymous_variant	1/12	ENST00000649764.2	NP_055555.1
EIF4A3	NM_001411099.1	c.90C>T	p.Thr30Thr	synonymous_variant	1/11		NP_001398028.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EIF4A3	ENST00000649764.2	c.90C>T	p.Thr30Thr	synonymous_variant	1/12		NM_014740.4	ENSP00000497641.1
EIF4A3	ENST00000647795.1	c.90C>T	p.Thr30Thr	synonymous_variant	2/13			ENSP00000497661.1
EIF4A3	ENST00000576547.2	c.90C>T	p.Thr30Thr	synonymous_variant	1/11	3		ENSP00000460439.2
EIF4A3	ENST00000575957.1	n.268C>T		non_coding_transcript_exon_variant	1/3	2

Frequencies

GnomAD3 genomes AF: 0.0125 AC: 1910 AN: 152214 Hom.: 38 Cov.: 33

Gnomad AFR AF: 0.0437

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00908

GnomAD3 exomes AF: 0.00298 AC: 735 AN: 246364 Hom.: 22 AF XY: 0.00225 AC XY: 302 AN XY: 134112

Gnomad AFR exome AF: 0.0398

Gnomad AMR exome AF: 0.00273

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000984

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000135

Gnomad OTH exome AF: 0.00166

GnomAD4 exome AF: 0.00122 AC: 1778 AN: 1459210 Hom.: 34 Cov.: 32 AF XY: 0.00105 AC XY: 763 AN XY: 726020

Gnomad4 AFR exome AF: 0.0391

Gnomad4 AMR exome AF: 0.00318

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000126

Gnomad4 OTH exome AF: 0.00305

GnomAD4 genome AF: 0.0126 AC: 1916 AN: 152322 Hom.: 38 Cov.: 33 AF XY: 0.0122 AC XY: 911 AN XY: 74482

Gnomad4 AFR AF: 0.0438

Gnomad4 AMR AF: 0.00457

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00899

Alfa AF: 0.00587 Hom.: 14

Bravo AF: 0.0145

Asia WGS AF: 0.00145 AC: 5 AN: 3474

EpiCase AF: 0.0000545

EpiControl AF: 0.000238

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	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	10
DANN	Benign	0.96
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

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: rs78918245; hg19: chr17-78120671;