8-143580164-G-A

Position:

chr8-143580164-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001130053.5(EEF1D):c.1753C>T(p.Arg585Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000725 in 1,613,600 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R585H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000074 ( 0 hom. )

Consequence

EEF1D
NM_001130053.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 5.58

Variant links:

Genes affected

EEF1D (HGNC:3211): (eukaryotic translation elongation factor 1 delta) This gene encodes a subunit of the elongation factor-1 complex, which is responsible for the enzymatic delivery of aminoacyl tRNAs to the ribosome. This subunit, delta, functions as guanine nucleotide exchange factor. It is reported that following HIV-1 infection, this subunit interacts with HIV-1 Tat. This interaction results in repression of translation of host cell proteins and enhanced translation of viral proteins. Several alternatively spliced transcript variants encoding multiple isoforms have been found for this gene. Related pseudogenes have been defined on chromosomes 1, 6, 7, 9, 11, 13, 17, 19.[provided by RefSeq, Aug 2010]

EEF1D links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.854

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EEF1D	NM_001130053.5 linkuse as main transcript	c.1753C>T	p.Arg585Cys	missense_variant	9/10	ENST00000618139.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	UniProt
EEF1D	ENST00000618139.4 linkuse as main transcript	c.1753C>T	p.Arg585Cys	missense_variant	9/10	5	NM_001130053.5	P29692-2
	ENST00000623257.1 linkuse as main transcript	n.1807G>A		non_coding_transcript_exon_variant	1/1
	ENST00000529247.1 linkuse as main transcript	n.268+261G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0000592

AC:

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000639

AC:

AN:

250586

Hom.:

AF XY:

0.0000664

AC XY:

AN XY:

135628

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000141

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000739

AC:

108

AN:

1461450

Hom.:

Cov.:

AF XY:

0.0000715

AC XY:

AN XY:

727016

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000926

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000592

AC:

AN:

152150

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74338

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000116

Hom.:

Bravo

AF:

0.0000604

ExAC

AF:

0.0000741

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 31, 2023

The c.1753C>T (p.R585C) alteration is located in exon 9 (coding exon 7) of the EEF1D gene. This alteration results from a C to T substitution at nucleotide position 1753, causing the arginine (R) at amino acid position 585 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Neurodevelopmental disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

May 25, 2020

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as 3A-VUS. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established, however it is suspected to be loss-of-function (PMID: 30787422; PMID: 28097321). (N) 0106 - This gene is known to be associated with autosomal recessive disease (PMID: 30787422; PMID: 28097321). (N) 0200 - Variant is predicted to result in a missense amino acid change from an arginine to a cysteine (exon 9). (N) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (18 heterozygotes, 0 homozygotes). (P) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (45 heterozygotes, 0 homozygotes). (N) 0501 - Missense variant consistently predicted to be damaging by multiple in-silico tools or highly conserved with a major amino acid change. (P) 0600 - Variant is located in an annotated domain or motif (EF-1 guanine nucleotide exchange domain; NCBI, Decipher, PDB). (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0807 - Variant has not previously been reported in a clinical context. (N) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1201 - Heterozygous variant detected in trans with a second likely pathogenic heterozygous variant in a recessive disease. (P) 1205 - Variant is maternally inherited. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.72

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.28

T;T;.;T;T;.;.;.;T;T;.;.;.;T;T

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.94

D;.;D;D;D;D;.;.;.;.;D;D;D;D;D

M_CAP

Benign

0.063

MetaRNN

Pathogenic

0.85

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.42

MutationAssessor

Pathogenic

3.2

M;M;.;.;.;.;.;.;M;M;.;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D;D;D;D;D

PrimateAI

Uncertain

0.73

PROVEAN

Pathogenic

-7.3

D;D;D;D;D;D;D;D;D;D;D;D;.;D;D

REVEL

Uncertain

0.57

Sift

Pathogenic

0.0

D;D;D;D;D;D;D;D;D;D;D;D;.;D;D

Sift4G

Uncertain

0.026

D;D;D;D;D;D;D;D;D;D;D;D;D;.;.

Polyphen

0.49

P;P;D;.;D;.;D;.;P;P;.;.;.;.;.

Vest4

0.95

MVP

0.80

MPC

0.64

ClinPred

0.92

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.78

gMVP

0.54

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over