Genetic Variant NM_004247.4:c.2813G>A (chr17-44851720-C-T) – ACMG Classification: Likely_pathogenic (9 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2PP2PP3_StrongPP5_Moderate

The NM_004247.4(EFTUD2):c.2813G>A(p.Arg938His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

EFTUD2
NM_004247.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P: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:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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, 0.967

PP5

Variant 17-44851720-C-T is Pathogenic according to our data. Variant chr17-44851720-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 1710737.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-44851720-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EFTUD2	NM_004247.4 link	c.2813G>A	p.Arg938His	missense_variant	Exon 27 of 28	ENST00000426333.7	NP_004238.3	Q15029-1B3KX19
EFTUD2	NM_001258353.2 link	c.2813G>A	p.Arg938His	missense_variant	Exon 27 of 28		NP_001245282.1	Q15029-1
EFTUD2	NM_001258354.2 link	c.2783G>A	p.Arg928His	missense_variant	Exon 27 of 28		NP_001245283.1	Q15029-3
EFTUD2	NM_001142605.2 link	c.2708G>A	p.Arg903His	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.2813G>A	p.Arg938His	missense_variant	Exon 27 of 28	1	NM_004247.4	ENSP00000392094.1		Q15029-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1413272

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

699676

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Aug 02, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26507355, 32333448, 34068052) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.82

D;.;D;.;.

Eigen

Pathogenic

0.90

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

.;D;D;D;D

M_CAP

Uncertain

0.15

MetaRNN

Pathogenic

0.97

D;D;D;D;D

MetaSVM

Uncertain

-0.0083

MutationAssessor

Pathogenic

3.9

H;.;H;.;.

PrimateAI

Pathogenic

0.92

PROVEAN

Pathogenic

-4.7

D;.;.;.;D

REVEL

Uncertain

0.52

Sift

Pathogenic

0.0

D;.;.;.;D

Sift4G

Pathogenic

0.0

D;D;D;D;D

Polyphen

1.0

D;.;D;.;.

Vest4

0.96

MutPred

0.82

Loss of MoRF binding (P = 0.0203);.;Loss of MoRF binding (P = 0.0203);.;.;

MVP

0.90

MPC

2.7

ClinPred

1.0

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.75

gMVP

0.98

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over