17-44851760-G-C

Position:

• chr17-44851760-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_004247.4(EFTUD2):​c.2773C>G​(p.Pro925Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,451,062 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: EFTUD2 NM_004247.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.27

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), EFTUD2. . Gene score misZ 4.0264 (greater than the threshold 3.09). Trascript score misZ 5.3556 (greater than threshold 3.09). GenCC has associacion of gene with mandibulofacial dysostosis-microcephaly syndrome.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EFTUD2	NM_004247.4	c.2773C>G	p.Pro925Ala	missense_variant	27/28	ENST00000426333.7	NP_004238.3
EFTUD2	NM_001258353.2	c.2773C>G	p.Pro925Ala	missense_variant	27/28		NP_001245282.1
EFTUD2	NM_001258354.2	c.2743C>G	p.Pro915Ala	missense_variant	27/28		NP_001245283.1
EFTUD2	NM_001142605.2	c.2668C>G	p.Pro890Ala	missense_variant	26/27		NP_001136077.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EFTUD2	ENST00000426333.7	c.2773C>G	p.Pro925Ala	missense_variant	27/28	1	NM_004247.4	ENSP00000392094	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1451062 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 721450

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: 9.02e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 12, 2024

The c.2773C>G (p.P925A) alteration is located in exon 27 (coding exon 26) of the EFTUD2 gene. This alteration results from a C to G substitution at nucleotide position 2773, causing the proline (P) at amino acid position 925 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.017	T
BayesDel_noAF	Benign	-0.21
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.61	D;.;D;.;.
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	.;D;D;D;D
M_CAP	Benign	0.040	D
MetaRNN	Uncertain	0.61	D;D;D;D;D
MetaSVM	Benign	-0.31	T
MutationAssessor	Pathogenic	3.2	M;.;M;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-6.2	D;.;.;.;D
REVEL	Uncertain	0.33
Sift	Uncertain	0.015	D;.;.;.;D
Sift4G	Uncertain	0.0040	D;D;D;D;D
Polyphen		1.0	D;.;D;.;.
Vest4		0.55
MutPred		0.26		Loss of glycosylation at P925 (P = 0.0617);.;Loss of glycosylation at P925 (P = 0.0617);.;.;
MVP		0.44
MPC		2.3
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.65
gMVP		0.72

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: rs923694972; hg19: chr17-42929128;