17-44851717-C-T

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP2PP3BS2

The NM_004247.4(EFTUD2):c.2816G>A(p.Arg939His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000095 in 1,578,860 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 (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000091 ( 0 hom. )

Consequence

EFTUD2
NM_004247.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.31

Variant links:

Genes affected

EFTUD2 (HGNC:30858): (elongation factor Tu GTP binding domain containing 2) This gene encodes a GTPase which is a component of the spliceosome complex which processes precursor mRNAs to produce mature mRNAs. Mutations in this gene are associated with mandibulofacial dysostosis with microcephaly. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]

EFTUD2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PP2

Missense variant in the EFTUD2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 21 curated pathogenic missense variants (we use a threshold of 10). The gene has 25 curated benign missense variants. Gene score misZ: 4.0264 (above the threshold of 3.09). Trascript score misZ: 5.3556 (above the threshold of 3.09). GenCC associations: The gene is linked to mandibulofacial dysostosis-microcephaly syndrome.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.8

BS2

High AC in GnomAdExome4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EFTUD2	NM_004247.4 link	c.2816G>A	p.Arg939His	missense_variant	Exon 27 of 28	ENST00000426333.7	NP_004238.3	Q15029-1B3KX19
EFTUD2	NM_001258353.2 link	c.2816G>A	p.Arg939His	missense_variant	Exon 27 of 28		NP_001245282.1	Q15029-1
EFTUD2	NM_001258354.2 link	c.2786G>A	p.Arg929His	missense_variant	Exon 27 of 28		NP_001245283.1	Q15029-3
EFTUD2	NM_001142605.2 link	c.2711G>A	p.Arg904His	missense_variant	Exon 26 of 27		NP_001136077.1	Q15029-2B3KX19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EFTUD2	ENST00000426333.7 link	c.2816G>A	p.Arg939His	missense_variant	Exon 27 of 28	1	NM_004247.4	ENSP00000392094.1		Q15029-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152094

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000478

AC:

AN:

209292

Hom.:

AF XY:

0.00000883

AC XY:

AN XY:

113256

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:

0.0000107

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000911

AC:

AN:

1426766

Hom.:

Cov.:

AF XY:

0.0000113

AC XY:

AN XY:

708052

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.0000110

Gnomad4 OTH exome

AF:

0.0000170

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152094

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74282

show subpopulations

Gnomad4 AFR

AF:

0.0000483

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:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.00000826

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Jul 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 939 of the EFTUD2 protein (p.Arg939His). This variant is present in population databases (rs763935473, gnomAD 0.005%). This variant has not been reported in the literature in individuals affected with EFTUD2-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt EFTUD2 protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.040

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.69

D;.;D;.;.

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

.;D;D;D;D

M_CAP

Uncertain

0.10

MetaRNN

Pathogenic

0.80

D;D;D;D;D

MetaSVM

Benign

-0.35

MutationAssessor

Pathogenic

3.4

M;.;M;.;.

PrimateAI

Pathogenic

0.91

PROVEAN

Pathogenic

-4.7

D;.;.;.;D

REVEL

Uncertain

0.41

Sift

Pathogenic

0.0

D;.;.;.;D

Sift4G

Pathogenic

0.0010

D;D;D;D;D

Polyphen

1.0

D;.;D;.;.

Vest4

0.65

MutPred

0.46

Loss of MoRF binding (P = 0.0349);.;Loss of MoRF binding (P = 0.0349);.;.;

MVP

0.80

MPC

2.7

ClinPred

0.99

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.80

gMVP

0.80

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

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