17-44851362-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP2 PP3

The NM_004247.4(EFTUD2):c.2831G>T(p.Ser944Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,398 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: EFTUD2 NM_004247.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.47

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PP2: Missense variant where missense usually causes diseases, EFTUD2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.817

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EFTUD2	NM_004247.4	c.2831G>T	p.Ser944Ile	missense_variant	28/28	ENST00000426333.7
EFTUD2	NM_001258353.2	c.2831G>T	p.Ser944Ile	missense_variant	28/28
EFTUD2	NM_001258354.2	c.2801G>T	p.Ser934Ile	missense_variant	28/28
EFTUD2	NM_001142605.2	c.2726G>T	p.Ser909Ile	missense_variant	27/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EFTUD2	ENST00000426333.7	c.2831G>T	p.Ser944Ile	missense_variant	28/28	1	NM_004247.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 250114 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135400

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: 0.00000886

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461398 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 727018

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: 0.0000126

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000470 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

EFTUD2-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 28, 2022

The EFTUD2 c.2831G>T variant is predicted to result in the amino acid substitution p.Ser944Ile. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.00089% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-42928730-C-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
Cadd	Pathogenic	30
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.70	D;.;D;.;.
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.82	D;D;D;D;D
MetaSVM	Benign	-0.55	T
MutationAssessor	Pathogenic	3.1	M;.;M;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-5.1	D;.;.;.;D
REVEL	Uncertain	0.54
Sift	Uncertain	0.0020	D;.;.;.;D
Sift4G	Uncertain	0.052	T;T;T;D;D
Polyphen		0.99	D;.;D;.;.
Vest4		0.64
MutPred		0.39		Loss of disorder (P = 0.0081);.;Loss of disorder (P = 0.0081);.;.;
MVP		0.50
MPC		2.5
ClinPred		1.0	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.70
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

Other links and lift over

dbSNP: rs1191076207; hg19: chr17-42928730;