chr17-44851728-G-C

Position:

• chr17-44851728-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_004247.4(EFTUD2):​c.2805C>G​(p.Ile935Met) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: EFTUD2 NM_004247.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.68

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.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.31634605).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EFTUD2	NM_004247.4	c.2805C>G	p.Ile935Met	missense_variant	27/28	ENST00000426333.7	NP_004238.3
EFTUD2	NM_001258353.2	c.2805C>G	p.Ile935Met	missense_variant	27/28		NP_001245282.1
EFTUD2	NM_001258354.2	c.2775C>G	p.Ile925Met	missense_variant	27/28		NP_001245283.1
EFTUD2	NM_001142605.2	c.2700C>G	p.Ile900Met	missense_variant	26/27		NP_001136077.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EFTUD2	ENST00000426333.7	c.2805C>G	p.Ile935Met	missense_variant	27/28	1	NM_004247.4	ENSP00000392094	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 18, 2022

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with EFTUD2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 935 of the EFTUD2 protein (p.Ile935Met). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.062	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	24
DANN	Benign	0.94
DEOGEN2	Benign	0.24	T;.;T;.;.
Eigen	Uncertain	0.23
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.97	.;D;D;D;D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.32	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L;.;L;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-2.0	N;.;.;.;N
REVEL	Benign	0.21
Sift	Benign	0.065	T;.;.;.;T
Sift4G	Benign	0.56	T;T;T;D;T
Polyphen		0.96	D;.;D;.;.
Vest4		0.75
MutPred		0.38		Gain of disorder (P = 0.0244);.;Gain of disorder (P = 0.0244);.;.;
MVP		0.26
MPC		2.2
ClinPred		0.74	D
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.47
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-42929096;